EP0135410A1 - Synergistin derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The invention provides new pristinamycin IIB derivatives of the formula: <IMAGE> (I) in which R represents alkylthio substituted by (i) alkylamino or dialkylamino of which the alkyl parts can form a pyrrolidin-1-yl, piperidino, azetidin-1-yl, azepin-1-yl, morpholino, thiomorpholino or piperazin-1-yl ring (optionally substituted by alkyl), or (ii) pyrrolidin-2-yl or pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4-yl, azetidin-2-yl or azetidin-3-yl or azepin-2-yl, azepin-3-yl or azepin-4-yl; a radical Het-S-, in which Het is pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl, azetidin-3-yl or azepin-3-yl or azepin-4-yl optionally N-alkylsubstituted; or dialkylamino of which the alkyl parts can form a pyrrolidin-1-yl, piperidino, azetidin-1-yl, azepin-1-yl, morpholino, thiomorpholino or piperazin-1-yl ring (optionally substituted by alkyl), the said alkyls having 1 to 5 carbon atoms each in a linear or branched chain. The compounds of the formula (I) are useful as antimicrobial agents when used in association with known synergistines or synergistines of the formula: <IMAGE> (V)

Description

leurs sels, leur préparation et les compositions pharmaceutiques qui les contiennent.The present invention relates to new pristinamycin II _b derivatives of general formula:

their salts, their preparation and the pharmaceutical compositions containing them.

• - soit un radical alcoylthio substitué :
  • - i) par un ou deux radicaux alcoylamino ou dialcoylamino dont les parties alcoyle peuvent éventuellement former ensemble avec l'atome d'azote auquel elles sont liées un hétérocycle saturé choisi parmi pyrrolidinyle-1, pipéridino, azétidinyle-1, azépinyle-1, morpholino, thiomorpholino et pipérazinyle-1 (éventuellement substitué par un radical alcoyle), ou bien
  • - ii) par un radical pyrrolidinyle-2 ou 3, pipéridyle-2, 3 ou 4, azétidinyle-2 ou 3 ou azépinyle-2, 3 ou 4,
• - soit un radical de formule générale :
  
  dans laquelle Het représente un radical pyrrolidinyle-3, pipéridyle-3 ou 4, azétidinyle-3 ou azépinyle-3 ou 4, (éventuellement substitués sur l'atome d'azote par un radical alcoyle)
• - soit un radical dialco^ylamino dont les parties alcoyle peuvent éventuellement former ensemble avec l'atome d'azote auquel elles sont liées un hétérocycle saturé choisi parmi pyrrolidinyle-1, pipéridino, azétidinyle-1, azépinyle-1, morpholino, thiomorpholino et pipérazinyle-1 (éventuellement substitué par un radical alcoyle), étant entendu que les radicaux alcoyle et portions alcoyle cités ci-dessus ou qui seront cités par la suite contiennent 1 à 5 atomes de carbone en chaîne droite ou ramifiée.

In the general formula (I), R represents

• - or a substituted alkylthio radical:
  • - i) by one or two alkylamino or dialkoylamino radicals, the alkyl parts of which may optionally form, together with the nitrogen atom to which they are linked, a saturated heterocycle chosen from pyrrolidinyl-1, piperidino, azetidinyl-1, azepinyl-1, morpholino , thiomorpholino and piperazinyl-1 (optionally substituted by an alkyl radical), or else
  • ii) by a pyrrolidinyl-2 or 3, piperidyl-2, 3 or 4, azetidinyl-2 or 3 or azeepinyl-2, 3 or 4 radical,
• - either a radical of general formula:
  
  in which Het represents a pyrrolidinyl-3, piperidyl-3 or 4, azetidinyl-3 or azeepinyl-3 or 4 radical (optionally substituted on the nitrogen atom by an alkyl radical)
• - or a dialco ^y lamino radical, the alkyl parts of which can optionally form, together with the nitrogen atom to which they are linked, a saturated heterocycle chosen from pyrrolidinyl-1, piperidino, azetidinyl-1, azepinyl-1, morpholino, thiomorpholino and pipérazinyle -1 (optionally substituted by an alkyl radical), it being understood that the alkyl radicals and alkyl portions mentioned above or which will be mentioned below contain 1 to 5 carbon atoms in a straight or branched chain.

It is understood that the products of general formula (1) may have isomeric forms and that these isomers and their mixtures fall within the scope of the present invention.

dans laquelle R est défini comme précédemment sur le produit de formule :

c'est-à-dire la pristinamycine II_A.According to the present invention, the products of general formula (1) can be prepared by the action of a product of general formula:

in which R is defined as above on the product of formula:

i.e. pristinamycin II _A.

The reaction is generally carried out without solvent or in an organic solvent such as an alcohol such as methanol or ethanol or a chlorinated solvent such as methylene chloride, 1,2-dichloroethane or chloroform, or in a mixture of these solvents (for example methylene chloride-methanol) at a temperature between 0 and 50 ° C.

It can sometimes be advantageous to operate in the presence of a tertiary amine, for example triethylamine, or an ethanolamine (dimethylethanolamine for example).

It is understood for a person skilled in the art that, when R represents a radical which contains a secondary amine function which may interfere with the reaction, this latter function must be protected beforehand before reacting the product of general formula (III) with the product of formula (IV). Any usual means that can block a secondary amine function can be used for this purpose in the form of a labile radical which can be eliminated after reaction of the product of general formula (III) with the product of formula (IV). It is particularly advantageous to use the trifluoroacetyl radical as blocking radical. This can then be removed using an aqueous solution of alkaline bicarbonate such as sodium or potassium bicarbonate.

The new products of general formula (1) can be purified by the usual known methods, for example crystallization, chromatography or successive extractions in acidic and basic medium. For those skilled in the art knowing the sensitivity of synergistins in an alkaline medium, the term "basic medium" means a medium which is just sufficiently alkaline to release the parent substance from its addition salt with an acid, that is to say a medium whose pH does not exceed 7.5 to 8.

It is well known that synergistins obtained by fermentation are products highly sought after by doctors for the treatment of many conditions due to Gram-positive bacteria (of the genus Staphylococci, Streptococci, pneumococci, enterococci) and Gram-negative bacteria genus Haemophilus, gonococci, meningococci). However, these products have the drawback of being insoluble in an aqueous medium and can therefore only be administered orally, generally in the form of capsules, dragees or tablets. Given this insolubility, it is impossible to use the synergistins known hitherto when the patient is not in a state to swallow; this is particularly the case in pediatrics and resuscitation, while the spectrum of activity of these products would make it a precious indication in a large number of circumstances, for example in cases of comatose septicemia.

dans laquelle Y représente un atome d'hydrogène ou un radical diméthylamino et

• 1) ou bien ---- représente une liaison simple, Z et R représentent un atome d'hydrogène et X représente un radical de formule générale :
  
  dans laquelle :
  • - soit R₂ représente un atome d'hydrogène et R₃ représente un radical hydroxy ou alcoyle éventuellement substitué par un radical carboxy, alcoyloxycarbonyle, hydroxy, alcoylamino ou dialcoylamino dont les radicaux alcoyle peuvent former avec l'atome d'azote auquel ils sont rattachés un hétérocycle à 4 à 7 chaînons choisi parmi azétidinyle, pyrrolidinyle, pipéridinyle, pipérazinyle, N-alcoylpipérazinyle ou azépinyle, ou bien R₃ représente un radical cycloalcoyle contenant 3 à 7 atomes de carbone ou un hétérocycle saturé à 4 à 7 chaînons choisi parmi les cycles azétidine, pyrrolidine, pipéridine et azépine, ces hétérocycles pouvant être éventuellement substitués sur l'atome d'azote par un radical alcoyle,
  • - soit R représente un radical formyle ou alcoylcarbonyle et R₃ représente un radical alcoyle substitué par un radical carboxy, alcoylamino ou dialcoylamino dont les radicaux alcoyle peuvent former avec l'atome d'azote auquel ils sont rattachés un hétérocycle à 4 à 7 chaînons choisi parmi azétidinyle, pyrrolidinyle, pipéridinyle, pipérazinyle, N-alcoylpipérazinyle ou azépinyle, ou bien R₃ représente un hétérocycle à 4 à 7 chaînons choisi parmi les cycles azétidine, pyrrolidine, pipéridine et azépine, ces hétérocycles pouvant être substitués sur l'atome d'azote par un radical alcoyle,
  • - soit R₂ et R₃, identiques ou différents, représentent un radical alcoyle éventuellement substitué par un radical carboxy, alcoyloxycarbonyle, hydroxy, alcoylamino ou dialcoylamino dont les radicaux alcoyle forment éventuellement avec l'atome d'azote auquel ils sont rattachés un hétérocycle à 4 à 7 chaînons choisi parmi azétidinyle, pyrrolidinyle, pipéridinyle, pipérazinyle, N-alcoylpipérazinyle ou azépinyle
  • - soit R₂ et Reforment ensemble avec l'atome d'azote auquel ils sont rattachés un hétérocycle à 4 à 7 chaînons choisi parmi les cycles azétidine, pyrrolidine, pipéridine, morpholine et pipérazine éventuellement substitué par un radical alcoyle,
• 2) ou bien ------- représente une double liaison, X représente un atome d'oxygène et Z représente un radical de formule générale :
  
  défini de la manière suivante :
  • a) soit R et R₅ représentent chacun un atome d'hydrogène et R₄ représente un radical pyrrolidinyl-3 thio ou pipéridyl-3 ou 4 thio (ces radicaux étant éventuellement substitués par un radical alcoyle) ou bien R₄ représente un radical alcoylthio substitué par un ou deux radicaux hydroxysulfonyle, alcoylamino, dialcoylamino (éventuellement substitué par un radical mercapto ou dialcoylamino) ou par un ou deux cycles choisis parmi pipérazino (éventuellement substitué par un radical alcoyle ou mercaptoalcoyle), morpholino, thiomorpholino, pipéridino, pyrrolidinyle-1, pipéridyle-2, 3 ou 4 et pyrrolidinyle-2 ou 3 (ces deux derniers cycles étant éventuellement substitués sur l'atome d'azote par un radical alcoyle),
  • b) soit R et R₅ forment ensemble une liaison de valence et R₄ représente un radical pyrrolidinyl-3 amino, pipéridyl-3 ou 4 amino, pyrrolidinyl-3 oxy, pipéridyl-3 ou 4 oxy, pyrrolidinyl-3 thio, pipéridyl-3 ou 4 thio (ces radicaux étant éventuellement substitués sur l'atome d'azote du cycle par un radical alcoyle), ou bien R₄ représente un radical alcoylamino, alcoyloxy ou alcoylthio substitués par un ou deux radicaux hydroxysulfonyle, alcoylamino, dialcoylamino (éventuellement substitué par un radical dialcoylamino), trialcoylammonio ou imidazolyle-4 ou 5 ou par un ou deux cycles choisis parmi pipérazino (éventuellement substitué par un radical alcoyle ou mercaptoalcoyle), morpholino, thiomorpholino, pipéridino, pyrrolidinyle-1, pipéridyle-2, 3 ou 4 et pyrrolidinyle-2 ou 3 (ces deux derniers cycles étant éventuellement substitués sur l'atome d'azote par un radical alcoyle), étant entendu que les radicaux alcoyle et portions alcoyle se rapportant aux symboles de la formule générale (V) contiennent 1 à 5 atomes de carbone et sont en chaîne droite ou ramifiée.

The new products according to the invention have the considerable advantage of being able to be solubilized in water, generally in the form of salts, at therapeutic doses which can be used and of enhancing the antibacterial action of pristinamycin I by a synergistic phenomenon. _A y of virginiamycin S or of soluble synergistin derivatives of general formula:

in which Y represents a hydrogen atom or a dimethylamino radical and

• 1) or ---- represents a single bond, Z and R represent a hydrogen atom and X represents a radical of general formula:
  
  in which :
  • - either R ₂ represents a hydrogen atom and R ₃ represents a hydroxy or alkyl radical optionally substituted by a carboxy, alkyloxycarbonyl, hydroxy, alkylamino or dialkoylamino radical in which the alkyl radicals can form with the nitrogen atom to which they are attached a 4- to 7-membered heterocycle chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl or azepinyl, or else R ₃ represents a cycloalkyl radical containing 3 to 7 carbon atoms or a saturated 4 to 7-membered heterocycle chosen from azetidine, pyrrolidine, piperidine and azepine rings, these heterocycles possibly being substituted on the nitrogen atom by an alkyl radical,
  • - either R represents a formyl or alkylcarbonyl radical and R ₃ represents an alkyl radical substituted by a carboxy, alkylamino or dialkoylamino radical in which the alkyl radicals can form, with the nitrogen atom to which they are attached, a chosen 4- to 7-membered heterocycle among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl or azepinyl, or else R ₃ represents a 4- to 7-membered heterocycle chosen from azetidine rings, pyrrolidine, piperidine and azepine, these heterocycles possibly being substituted on the nitrogen atom by an alkyl radical,
  • - either R ₂ and R ₃ , identical or different, represent an alkyl radical optionally substituted by a carboxy, alkyloxycarbonyl, hydroxy, alkylamino or dialkoylamino radical in which the alkyl radicals optionally form with the nitrogen atom to which they are attached a heterocycle to 4- to 7-membered chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl or azepinyl
  • either R ₂ and Reform together with the nitrogen atom to which they are attached a 4- to 7-membered heterocycle chosen from the azetidine, pyrrolidine, piperidine, morpholine and piperazine rings optionally substituted by an alkyl radical,
• 2) or ------- represents a double bond, X represents an oxygen atom and Z represents a radical of general formula:
  
  defined as follows:
  • a) either R and R ₅ each represent a hydrogen atom and R ₄ represents a pyrrolidinyl-3 thio or piperidyl-3 or 4 thio radical (these radicals being optionally substituted by an alkyl radical) or else R ₄ represents an alkylthio radical substituted by one or two hydroxysulfonyl, alkylamino, dialkoylamino radicals (optionally substituted by a mercapto or dialkoylamino radical) or by one or two rings chosen from piperazino (optionally substituted by an alkyl or mercaptoalkyl radical), morpholino, thiomorpholino, piperidino-1 , piperidyl-2, 3 or 4 and pyrrolidinyl-2 or 3 (these last two cycles being optionally substituted on the nitrogen atom by an alkyl radical),
  • b) or R and R ₅ together form a valence bond and R ₄ represents a pyrrolidinyl-3 amino, piperidyl-3 or 4 amino radical, pyrrolidinyl-3 oxy, piperidyl-3 or 4 oxy, pyrrolidinyl-3 thio, piperidyl- 3 or 4 thio (these radicals being optionally substituted on the nitrogen atom of the ring by an alkyl radical), or else R ₄ represents a substituted alkylamino, alkyloxy or alkylthio radical by one or two hydroxysulfonyl, alkoylamino, dialcoylamino (optionally substituted by a dialcoylamino), trialcoylammonio or imidazolyle-4 or 5 radicals or by one or two rings chosen from piperazino (optionally substituted by an alkyl or mercaptoalkyl), morpholino, thiomorpholino, piperidino, pyrrolidinyle-1, pipéridyle-2, 3 or 4 and pyrrolidinyle-2 or 3 (these last two cycles being optionally substituted on the nitrogen atom by an alkyl radical), it being understood that the alkyl radicals and alkyl portions are referring to the symbols of the general formula (V) contain 1 to 5 carbon atoms and are in a straight or branched chain.

Some of the synergistin derivatives of general formula (V) may have isomeric forms. It is understood that these isomeric forms as well as their mixtures can be advantageously combined with the products of general formula (I).

dans laquelle R₂ et R₃ sont définis comme ci-dessus, sur une synergistine de formule générale :

dans laquelle Y représente un atome d'hydrogène (virginiamycine S) ou le radical diméthylamino (pristinamycine I_A), en présence d'un cyanoborohydrure alcalin.The products of general formula (V) defined as above in 1) with the exception of those for which R ₂ represents a formyl or alkylcarbonyl radical, can be prepared by the action of an amine of general formula:

in which R ₂ and R ₃ are defined as above, on a synergistin of general formula:

in which Y represents a hydrogen atom (virginiamycin S) or the dimethylamino radical (pristinamycin I _A ), in the presence of an alkaline cyanoborohydride.

The operation is generally carried out with an excess of amine of general formula (VIII) in the presence of an alkaline cyanoborohydride such as sodium cyanoborohydride, in an organic solvent such as an alcohol in which gaseous hydrochloric acid (methanol) has been dissolved. hydrochloric acid or hydrochloric ethanol), at a temperature between 0 ° C and the reflux temperature of the reaction mixture, preferably at a temperature in the region of 20 ° C.

The reaction can advantageously be carried out in the presence of a drying agent such as molecular sieves.

dans laquelle R₆représente un atone d'hydrogène ou un radical alcoyle et Q représente un atome d'halogène ou un radical alcoylcarbonyloxy, sur un produit de formule générale :

dans laquelle Y est défini comme précéderiment et R'₃ a la définition de R₃ correspondante dcnnée ci-dessus.The products of general formula (V) defined as above in 1) in which R ₂ represents a formyl or alkylcarbonyl radical and R ₃ represents an alkyl radical substituted by a carboxy, alkylamino or dialkoylamino radical in which the alkyl radicals optionally form with the atom nitrogen to which they are attached, a 4- to 7-membered heterocycle chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, alkylpiperazinyl or azepinin, or represents a saturated 4- to 7-membered heterocycle chosen from the azetidine, pyrrolidine, piperidine and azepine rings , these heterocycles which can be substituted on the nitrogen atom by an alkyl radical, and Y is defined as above, can be prepared by the action of a product of general formula:

in which R ₆ represents a hydrogen atom or an alkyl radical and Q represents a halogen atom or an alkylcarbonyloxy radical, on a product of general formula:

in which Y is defined as previous and R ' ₃ has the corresponding definition of R ₃ given above.

The reaction is generally carried out in an organic solvent such as pyridine, in a chlorinated solvent (methylene chloride) or an ether (tetrahydrofuran) in the presence of an acid acceptor such as an organic base such as triethylamine or a mineral base such as a carbonate or an alkaline bicarbonate such as sodium bicarbonate, operating at a temperature between 0 ° C and 80 ° C.

It is understood for a person skilled in the art that, when R ′ ₃ represents a radical containing a secondary amine function, said function must be protected before reacting the product of general formula (X) with the product of general formula (XI) . Any usual blocking means used to protect an amine function are used for this purpose and can be eliminated subsequently, without affecting the rest of the molecule. It is particularly advantageous to use as a blocking radical the trifluoroacetyl radical; this can then be removed using an aqueous solution of alkaline bicarbonate such as sodium or potassium bicarbonate.

It is also understood for those skilled in the art that, when in the general formula (VIII) R ₂ and / or R ₃ represent a radical containing a secondary amine function, the latter must be protected beforehand before reacting the product of formula general (VIII) on the product of general formula (IX). Locking and unlocking are carried out as described above.

dans laquelle R'₄ a la définition de R₄ donnée précédemment en 2)a) sur un produit de formule générale :

dans laquelle Y est défini comme précédemment.The products of general formula (V) defined as previously in 2) in which Y is defined as previously and the other symbols are defined as previously in 2) a) can be prepared by the action of a product of general formula:

in which R ' ₄ has the definition of R ₄ given above in 2) a) on a product of general formula:

in which Y is defined as above.

It is generally carried out in an organic solvent such as an alcohol such as methanol or a chlorinated solvent such as chloroform or a mixture of these solvents, at a temperature between 0 ° C. and the reflux temperature of the reaction mixture, preferably at a temperature close to 20 ° C.

dans laquelle Y est défini comme précédemment.The products of general formula (XIII) can be prepared by the action of an alkaline borohydride such as sodium cyanoborohydride on a product of general formula:

in which Y is defined as above.

It is generally carried out in an organic solvent such as an ether such as tetrahydrofuran or an alcohol, for example isopropanol, in the presence of an acid such as trifluoroacetic acid, at a temperature between 0 ° C. and the temperature of reflux of the reaction mixture, preferably at a temperature in the region of 20 ° C.

dans laquelle ou bien X₁ représente un radical alcoyloxy et X₂ représente un radical alcoyloxy ou diméthylamino, ou bien X₁ et X₂ représentent tous les deux un radical diméthylamino, sur un produit de formule générale (IX).The products of general formula (XIV) can be obtained by the action of a product of formula:

in which either X ₁ represents an alkyloxy radical and X ₂ represents an alkyloxy or dimethylamino radical, or else X ₁ and X ₂ both represent a dimethylamino radical, on a product of general formula (IX).

In practice, it is advantageous to react tert-butoxy bis (dimethylamino) methane on the product of general formula (IX), operating in an organic solvent such as a chlorinated solvent such as 1,2-dichloroethane or an amide (dimethylformamide for example) at a temperature between 0 ° C and 80 ° C, preferably at a temperature in the region of 20 ° C.

The products of general formula (XV) can be prepared according to the methods described by H. BREDERECK et al., Chem. Ber., 101, 41 and 3058 (1968) and Chem. Ber., 106, 3725 (1973).

dans laquelle R"₄ a la définition de R₄ donnée ci-dessus, sur un produit de formule générale (XIV) dans laquelle Y est défini comme précédemment.The products of general formula (V) in which Y is defined as above and the other symbols are defined as above in 2) b) with the exception for R ₄ of representing a pyrrolidinyl-3 oxy, piperidyl-3 or 4 oxy radical or optionally substituted alkyloxy as defined in 2) b), can be prepared by the action of a product of general formula:

in which R " ₄ has the definition of R ₄ given above, on a product of general formula (XIV) in which Y is defined as above.

The reaction is carried out in an organic medium, in the presence of an acid (for example acetic acid or a mixture of acetic acid and catalytic amounts of trifluoroacetic acid), in the presence or not of a solvent, at a temperature between 0 and 50 ° C; preferably at a temperature close to 20 ° C.

Where appropriate, the solvent can be chosen from organic solvents such as ethers (tetrahydrofuran), alcohols (ethanol) and chlorinated solvents (methylene chloride or chloroform for example).

dans laquelle R"'₄ est défini comme R₄ en 2) b), sur un produit de formule générale :

dans laquelle Y est défini comme précédemment et Z_lreprésente un radical tosyloxy, acétyloxy, triméthylsilyloxy ou dialcoyloxy- phosphoryloxy dont les parties alcoyle contiennent 1 à 4 atomes de carbone en chaîne droite ou ramifiée, ou bien Z₁ représente un atome de chlore.The products of general formula (f) in which Y is defined as above and the other symbols are defined as previously in 2) b) can be prepared by the action of a product of general formula:

in which R "' ₄ is defined as R ₄ in 2) b), on a product of general formula:

in which Y is defined as above and Z _l represents a tosyloxy, acetyloxy, trimethylsilyloxy or dialkoyloxyphosphoryloxy radical in which the alkyl parts contain 1 to 4 carbon atoms in a straight or branched chain, or else Z ₁ represents a chlorine atom.

It is generally carried out in an organic solvent such as an ether such as tetrahydrofuran, an alcohol such as ethanol or a chlorinated solvent (methylene chloride or chloroform for example) at a temperature in the region of 20 ° C. The reaction is carried out in a basic medium, for example in the presence of an alkali hydride or an alkali alcoholate such as sodium ethylate or potassium tert-butoxide.

When R "' ₄ is other than substituted alkoxy or heterocyclyloxy, it is also possible to operate either in a neutral medium at a temperature between 0 and 50 ° C., in one of the solvents mentioned above, or in an acid medium under conditions identical to those described above for the action of a product of general formula (XVI) on a product of general formula (XIV).

suivie :

• α) ou bien de l'action d'un produit de formule générale :
  
  dans laquelle X représente un atome d'halogène et Z'₁ a la définition donnée précédemment pour Z₁ à l'exception de représenter un atome de chlore
• β) ou bien de l'action d'un produit de formule :
  
  pour obtenir un produit de formule générale (XVIII) dans laquelle Z₁ représente un atome de chlore.

The products of general formula (XVIII) can be prepared by acid hydrolysis of a product of general formula (XIV) to obtain a product of general formula:

followed:

• α) or the action of a product of general formula:
  
  in which X represents a halogen atom and Z ' ₁ has the definition given above for Z ₁ with the exception of representing a chlorine atom
• β) or the action of a product of formula:
  
  to obtain a product of general formula (XVIII) in which Z ₁ represents a chlorine atom.

The hydrolysis of the product of general formula (XIV) into product of general formula (XVIII) is carried out by means of an aqueous solution of a mineral acid such as an 0.1N aqueous solution of hydrochloric acid, operating at a temperature close to 20 ° C.

The reaction of the product of general formula (XX) with the product of general formula (XIX) is generally carried out in an organic solvent such as methylene chloride in the presence of an acid acceptor such as an organic base such as triethylamine or a mineral base such as a carbonate or an alkaline bicarbonate, for example sodium bicarbonate or potassium. We generally operate at a temperature between -20 and + 20 ° C.

The reaction of the product of general formula (XXI) with the product of general formula (XIX) is generally carried out in a chlorinated solvent such as methylene chloride at a temperature between -20 and + 20 ° C.

• - G.G. Urquart et coll., Org. Synth., 21, 36 (1941)
• - A.I. Vogel, J. Chem. Soc., 1822 (1948)
• - J.H. Chapman et L.N. Owen, J. Chem. Soc., 579 (1950)
• - H.R. Snyder et coll., J. Am. Chem. Soc., 69, 2672 (1947)
• - D.D. Reynolds et coll., J. Org. Chem., 26, 5125 (1961)
• - J.W. Haeffele et coll., Proc. Sci. Toilet Goods Assoc., 32, 52(1959)
• - H. Barrer et coll., J. Org. Chem., 27, 641 (1962)
• - J.H. Biel et coll., J. Amer. Chem. Soc., 77, 2250 ( 1955)

The products of general formulas (III), (VIII), (XII), (XVI) and (XVII) can be prepared according to or by analogy with the methods described below in the examples and in particular according to:

• - GG Urquart et al., Org. Synth., 21, 36 (1941)
• - AI Vogel, J. Chem. Soc., 1822 (1948)
• - JH Chapman and LN Owen, J. Chem. Soc., 579 (1950)
• - HR Snyder et al., J. Am. Chem. Soc., 69, 2672 (1947)
• - DD Reynolds et al., J. Org. Chem., 26, 5125 (1961)
• - JW Haeffele et al., Proc. Sci. Toilet Goods Assoc., 32, 52 (1959)
• - H. Barrer et al., J. Org. Chem., 27, 641 (1962)
• - JH Biel et al., J. Amer. Chem. Soc., 77, 2250 (1955)

• - B.K. Campbell et K.N. Campbell, J. Amer. Chem. Soc., 60, 1372 (1938)
• - R.C. Elderfield et coll., J. Amer. Chem. Soc., 68, 1579 (1946) lorsqu'il s'agit d'un produit de formule générale (XVI) ou (XVII) pour lequel R"₄ ou R"'₄ représente un radical alcoyloxy substitué ou hétéro- cyclyloxy, ou selon :
• - J. Amer. Chem. Soc., 54, 1499 (1932) et
• - J. Amer. Chem. Soc., 54, 3441 (1932),

in the case of a product of general formula (III), (XII), (XVI) or (XVII) for which R, R ' ₄ , R " ₄ or R"' 4 represents a substituted alkylthio radical or heterocyclylthio, or according to: AJW Headlee et al., J. Amer. Chem. Soc., 55, 1066 (1933)

• - BK Campbell and KN Campbell, J. Amer. Chem. Soc., 60, 1372 (1938)
• - RC Elderfield et al., J. Amer. Chem. Soc., 68, 1579 (1946) in the case of a product of general formula (XVI) or (XVII) for which R " ₄ or R"' ₄ represents a substituted alkyl or heterocycloxy radical, or according to:
• - J. Amer. Chem. Soc., 54, 1499 (1932) and
• - J. Amer. Chem. Soc., 54, 3441 (1932),

• - E.F. Elslager et coll., J. Med. Chem., 17, 99 (1974)
• - L.M. Werbel et coll., J. Het. Chem., 10, 363 (1973),

in the case of a product of general formula (VIII) or of general formula (III), (XVI) or (XVII) for which R, R " ₄ or R"' ₄ are substituted alkylamino radicals, or according to:

• - EF Elslager et al., J. Med. Chem., 17, 99 (1974)
• - LM Werbel et al., J. Het. Chem., 10, 363 (1973),

when it is a product of general formula (III), (XVI) or (XVII) for which R, R " ₄ or R"' ₄ are heterocyclylamino radicals.

It is understood that in the above methods, when _R2 , R ₃₅ R ' ₄ , R " ₄ or R"' ₄ contain an alkyllarnino radical which can interfere with the reaction, the latter is previously protected by any known method which does not not alter the rest of the molecule.

Likewise when the radicals R ' ₄ , R " ₄ and R"' ₄ in the products of general formulas (XII), (XVI) and (XVII) contain a secondary amine function which can interfere with the reaction, the latter must be protected before reacting the corresponding products respectively with the products of general formulas (XIII), (XIV) and (XVIII). The protective radical is removed after reaction. This is carried out for this purpose under the conditions described above for the radical R of the reagent of general formula (III).

Where appropriate, the isomers of the products of general formula (I) and / or of the products of general formula (V) can be separated by chromatography or by high performance liquid chromatography.

The products of general formula (V) can be purified as mentioned previously for the products of general formula (I).

In the laboratory, the products of general formula (1) synergize the antimicrobial action of the products of general formula (V) at doses between 5 and 200 mg / kg in mice subcutaneously, especially in sepsis caused by Staphylococcus aureus Smith when mixed with products of general formula (V) in proportions varying between 10-90% and 90-10%.

The acute toxicity of the products of general formula (I), expressed by the LD ₅₀ , is generally between 300 and 900 mg / kg subcutaneously in mice.

• parmi ces produits plus spécialemnt intéressants sont les produits de formule générale (I) dans laquelle R est un radical alcoylthio ramifié contenant 1 à 3.atomes de carbone substitué par un radical dialcoylamino

Of particular interest for their good synergistic effect with respect to pristinamycin I _A , are the products of general formula (1) in which R represents an alkylthio radical substituted by one or two dialkoylamino radicals of which the alkyl parts may optionally form with the nitrogen atom to which they are attached, a saturated heterocycle chosen from pyrrolidinyl-1 and piperazinyl-1 optionally substituted by an alkyl radical, or else R represents either a radical of general formula (II) in which Het represents a piperidyl-4 radical optionally substituted on the nitrogen atom by an alkyl radical, or a dialkoylamino radical of which the alkyl parts may form with the nitrogen atom to which they are linked, a piperazinyl-1 ring optionally substituted by an alkyl radical, it being understood that the radicals and alkyl portions mentioned above are straight or branched and contain 1 to 3 carbon atoms ;

• among these more particularly interesting products are the products of general formula (I) in which R is a branched alkylthio radical containing 1 to 3 carbon atoms substituted by a dialkoylamino radical

• - (diéthylamino-1 propyl-2) thio-26 pristinamycine Ils
• - (méthyl-4 pipérazinyl-l)-26 pristinamycine IlS.

or represents a 4-alkyl-piperazinyl-1 ring, it being understood that, unless otherwise mentioned, the alkyl radicals contain 1 or 2 carbon atoms; and in particular the following products:

• - (1-diethylamino-2-propyl) thio-26 pristinamycin They
• - (4-methyl-piperazinyl-1) -26 pristinamycin IlS.

For therapeutic use, use may be made of the new products according to the invention as they are, that is to say in the basic state in combination with synergistins already known, but as the main advantage of the products according to the invention. invention is their possible solubilization in water, it is particularly advantageous to use them in the form of pharmaceutically acceptable salts, in association with known synergistins or the synergistins of general formula (V) themselves solubilized either in the state of pharmaceutically acceptable salts is, where appropriate, in the basic state when the solubility is sufficient for the solution obtained to contain an amount of product at least equal to the therapeutically active dose.

As pharmaceutically acceptable salts, both for the products of general formula (1) and for the products of general formula (V), mention may be made of addition salts with mineral acids such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates , or organic such as acetates, propionates, succinates, maleates, fumarates, methanesulfonates, p.toluene sulfonates, isethionates or substitution derivatives of these compounds. As pharmaceutically acceptable salts, mention may also be made of the salts with alkali metals such as the sodium, potassium and lithium salts, with the alkaline earth metals such as the magnesium salt, the ammonium salt and the salts of addition with organic nitrogen bases: ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dibenzylamine, dicyclohexylbenzylamine, N-benzyl-B-phenethylamine, NN'-dibenzylethylene-diamine , benzhydrylamine, arginine, leucine, lysine or N-methyl-glucamine.

As pharmaceutically acceptable salts for the products of general formula (V) in which Z represents a radical of general formula (VII) in which R ₄ represents a trialkylammonio radical, mention may be made of the quaternary ammonium salts corresponding to the anions listed above .

The following examples, given without limitation, show how the invention can be put into practice. The NMR spectra of the products illustrated in these examples and in the reference examples which follow, present general characteristics which are common to all the products of general formula (1) or of general formula (V) and particular characteristics which are specific to each product depending on the substituents. In Example 1, as well as in Reference Examples 1 and 16, the assignment of all the protons of the molecule is given; in the following examples or reference examples only the particular characteristics due to the variable radicals are mentioned. For the products of general formula (I) all the protons are designated according to the numbering indicated in the following formula:

For synergistins of general formula (V) all the protons are designated according to the numbering indicated in the general formula (XXIII); this numbering is that recommended by JO ANTEUNIS et al., [Eur. J. Biochem., 58, 259 (1975)].

• s = singulet
• d ⁼ doublet
• t = triplet
• mt = multiplet
• m = massif
• dd = doublet de doublet
• dt = doublet de triplet
• ddd = doublet de doublet de doublet
• dddd = doublet de doublet de doublet de doublet

All the spectra were made at 250 MHz in deuterochloroform; the chemical shifts are expressed in ppm relative to the tetramethylsilane signal. The abbreviations used below are as follows:

• s = singlet
• d ⁼ doublet
• t = triplet
• mt = multiplet
• m = massive
• dd = doublet of doublet
• dt = triplet doublet
• ddd = doublet of doublet of doublet
• dddd = doublet of doublet of doublet of doublet

In the examples which follow, a "flash" chromatography is a purification technique characterized in that a short chromatography column is used and that the operation is carried out under a medium pressure (50 kPa) using a silica with a particle size of 40-53. um, according to WC STILL, M. KAHN and A.MITRA. [J. Org. Chem., 43, 2923 (1978)].

EXAMPLE 1

To a suspension of 13.1 g of pristinamycin II _A in 150 cm 3 of methanol, a solution of 3.7 g of diethylamino ethanethiol in 15 cm 3 of methylene chloride is added. The solution obtained is stirred for 18 hours at a temperature in the region of 20 ° C, then poured into 1500 cm3 of distilled water; the mixture obtained is extracted 3 times with 1000 cm 3 in total of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is purified by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume)]; after dry concentration of fractions 5 to 23 under reduced pressure (2.7 kPa) at 30 ° C, 12.4 g of (2-ethyl diethylamino) thio-26 pristinamycin II _B are obtained in the form of a yellow fondant powder around 105 ° C.

A 2% aqueous solution of (diethylamino-2 ethyl) thio-26 pristinamycin II _B (product BA), in the form of hydrochloride, is obtained with:

EXAMPLE 2

By operating in a manner analogous to that described in Example 1, but using 2.7 g of pristinamycin II _A and 0.58 g of 2-dimethylaminoethanethiol and after purification by "flash" chromatography [eluent: chloroform -methanol (90-10 by volume)] and dry concentration of fractions 11 to 17 under reduced pressure (2.7 kPa) at 30 ° C, 1.1 g of (2-dimethylamino ethyl) thio-26 pristinamycin are obtained II _B in the form of a yellow powder melting at around 100 ° C.

• ₂,35 (s, 6H : -N(CH₃)₂)
• 2,80 (m, 4H : -S-CH₂CH₂-N )
• 3,40 (ddd, 1H : H 26)
• 4,75 (d, 1H : H 27)
• 8,10 (s, 1H : H 20)

NMR spectrum:

• _2, 35 (s, 6H: N (CH _{3) 2)}
• 2.80 (m, 4H: -S-CH ₂ CH ₂ -N)
• 3.40 (ddd, 1H: H 26)
• 4.75 (d, 1H: H 27)
• 8.10 (s, 1H: H 20)

A 2% aqueous solution of (2-dimethylaminoethyl) thio-26 pristinamycin II _B (product BB), in the form of hydrochloride, is obtained with:

EXAMPLE 3

By following a procedure analogous to that described in Example 1, but using 5.25 g of pristinamycin II _A and 1.3 g of 3-dimethylamino propanethiol and after purification by "flash" chromatography [eluent: chloroform -methanol (90-10 by volume)] and dry concentration of fractions 6 to 29 under reduced pressure (2.7 kPa) at 30 ° C, 3.3 g of (3-dimethylamino propyl) thio-26 pristinamycin are obtained II _B in the form of a yellow powder melting at around 100 ° C.

• 1,50 (s, 3H x 0,5 : H 33 1er isomère)
• 1,70 (s, 3H x 0,5 : H 33 2ème isomère)
• 1,80 (m, -2H : -SCH₂-CH₂-CH₂N)
• 2,20 (s, 6H x 0,5 : -N(CH₃)₂ ler isomère)
• 2,25 (s, 6H x 0,5 : -N(CH₃)₂ 2ème isomère)
• 2,40 (m, 2H : -SCH₂-CH₂-CH₂N)
• 2,70 (m, 2H : -SCH₂-CH₂-CH₂N)
• 3,35}
• 3,45
• 3,45 (2m, 1H : H 26 de chaque isomère)
• 4,60) (2d, 1H : H 27 de chaque isomère)
• 4,70
• 7,80} (2s, 1H : H 20 de chaque isomère)
• 8,10

NMR spectrum:

• 1.50 (s, 3H x 0.5: H 33 1st isomer)
• 1.70 (s, 3H x 0.5: H 33 2nd isomer)
• 1.80 (m, -2H: -SCH ₂ -CH ₂ -CH ₂ N)
• 2.20 (s, 6H x 0.5: -N (CH ₃ ) _2nd isomer)
• 2.25 (s, 6H x 0.5: -N (CH ₃ ) ₂ 2nd isomer)
• 2.40 (m, 2H: -SCH ₂ -CH ₂ -CH ₂ N)
• 2.70 (m, 2H: -SCH ₂ -CH ₂ -CH ₂ N)
• 3.35}
• 3.45
• 3.45 (2m, 1H: H 26 of each isomer)
• 4.60) (2d, 1H: H 27 of each isomer)
• 4.70
• 7.80} (2s, 1H: H 20 of each isomer)
• 8.10

A 3.3% aqueous solution of (3-dimethylamino propyl) thio-26 pristinamycin II _B (product BC) is obtained, with:

EXAMPLE 4

By operating in a manner analogous to that described in Example 1, but starting from 5.25 g of pristinamycin II _A and 1.7 g of (pyrrolidinyl-1) -2 ethanethiol and after purification by "flash" chromatography [eluent: chloroform-methanol (95-5 by volume) J and dry concentration of fractions 19 to 60 under reduced pressure (2.7 kPa) at 30 ° C, 3.9 g of [(pyrrolidinyl-1) are obtained -2 ethyl] thio-26 pristinamycin II _B in the form of a yellow powder, melting at around 115 ° C.

• 1,90 (mt, 4H :
  
• 2,50 à 2,80 (m, 6H :
  
• 3,40 (d, 1H : H 26)
• 4,75 (d, 1H : H 27)
• 8,10 (s, 1H : H 20)

NMR spectrum:

• 1.90 (mt, 4H:
  
• 2.50 to 2.80 (m, 6H:
  
• 3.40 (d, 1H: H 26)
• 4.75 (d, 1H: H 27)
• 8.10 (s, 1H: H 20)

A 5% aqueous solution of [pyrrolidinyl-1) -2 ethyl] thio-26 pristinamycin II _B (product BD) is obtained, in the hydrochloride state, with:

(Pyrrolidinyl-1) -2 ethanethiol can be prepared according to the method described by JW HAEFFELE and RW BROGE, Proc. Sci. _T oilet Goods Assoc. 32, 52 (1959) [Chem. Abstr. 54, 17234e (1960) 7.

EXAMPLE 5

By operating in a manner analogous to that described in Example 1, but starting from 3.15 g of pristinamycin II _A and 1.1 g of (2-mercapto-ethyl) -1 methyl-4 piperazine and after purification by "flash" chromatography [eluent: chloroform-methanol (95-5 by volume)] and dry concentration of fractions 14 to 20 under reduced pressure (2.7 kPa) at 30 ° C, 1.4 g of [( 4-methyl-piperazinyl-1) -2 ethyl] thio-26 pristinamycin II _B in the form of a yellow powder, melting at around 115 ° C.

• 2,30 (s, 3H : N-CH₃)
• 2,40 à 2,80 (m, 12H :
  
• 3,35 (d, 1H : H 26)
• 4,75 (d, 1H : H 27)
• 8,10 (s, 1H : H 20)

NMR spectrum:

• 2.30 (s, 3H: N-CH ₃ )
• 2.40 to 2.80 (m, 12H:
  
• 3.35 (d, 1H: H 26)
• 4.75 (d, 1H: H 27)
• 8.10 (s, 1H: H 20)

A 2% aqueous solution of [(methyl-4 piperazinyl-1) -2 ethyl7 thio-26 pristinamycin II _B (product BE), in hydrochloride form, is obtained with:

(Mercapto-2 ethyl) -1 methyl-4 piperazine can be prepared according to the method described by D.D. REYNOLDS et al., J. Org. Chem., 26, 5125 (1961).

EXAMPLE 6

By operating in a manner analogous to that described in Example 1, but starting from 3.15 g of pristinamycin II _A and 1.8 g of diethylamino-1 propanethiol-2 and after purification by "flash" chromatography [eluent : methylene chloride-methanol (90-10 by volume)] and dry concentration of fractions 3 3 5 under reduced pressure (2.7 kPa) at 30 ° C, 1.4 g of (1-diethylamino-2-propyl) thio-26 pristinamycin II _B are obtained in the form of a yellow powder melting around 160 ° C.

• 1 (m, 9H : H 32 ⁺ -N(CH₂CH₃)₂)
• 2,50 (m, 6H : -CH₂N(CH₂CH₃)₂)
• 3,30 (m, 1H : H 26)
• 4,70 (d, 1H : H 27)
• 8,12 (s, 1H : H 20)

NMR spectrum:

• 1 (m, 9H: H 32 ⁺ -N (CH ₂ CH ₃ ) ₂ )
• 2.50 (m, 6H: -CH ₂ N (CH ₂ CH ₃ ) ₂ )
• 3.30 (m, 1H: H 26)
• 4.70 (d, 1H: H 27)
• 8.12 (s, 1H: H 20)

A 5% aqueous solution of (diethylamino-1 propyl-2) thio-26 pristinamycin II _B (product _BF ) is obtained, in the hydrochloride state, with:

Diethylamino-1 propanethiol-2 can be prepared by the method described by R.T. WRAGG, J. Chem. Soc. (C), 16, 2087 (1969).

EXAMPLE 7

By following a procedure analogous to that described in Example 1, but starting from 3.15 g of pristinamycin II _A and 1.6 g of methyl-1 piperidinethiol-4 and addition of 0.6 g of triethylamine to the reaction mixture and after purification by "flash" chromatography [eluent: methylene chloride-methanol (92-8 by volume)] and dry concentration of fractions 4 to 20 under reduced pressure (2.7 kPa) at 30 ° C, 0.9 g of (methyl-1 piperidinyl-4) thio-26 pristinamycin II _{B is} obtained in the form of a yellow powder melting at around 180 ° C.

• 2,10 (m, 4H : -S.
  
• 2,25 (s, 3H : -S
  
• 2,80 (m, 4H : -S
  
• 3,55 (m, 1H : H 26)
• 4,62 (m, 1H : H 27)
• 7,70 (m, 1H : H 8)
• 8,10 (s, 1H : H 20)

NMR spectrum:

• 2.10 (m, 4H: -S.
  
• 2.25 (s, 3H: -S
  
• 2.80 (m, 4H: -S
  
• 3.55 (m, 1H: H 26)
• 4.62 (m, 1H: H 27)
• 7.70 (m, 1H: H 8)
• 8.10 (s, 1H: H 20)

A 5% aqueous solution of 1-methyl-piperidinyl-4) thio-26 pristinamycin II _B (product BG) is obtained, in the hydrochloride state, with:

1-methyl-piperidinethiol-4 can be prepared by the method described by H. BARRER and R.E. LYLE, J. Org. Chem., 27, 641 (1962).

EXAMPLE 8

By operating in a manner analogous to that described in Example 1, but starting with 5.25 g of pristinamycin II _A and 10 cm 3 of a 5N ethanolic solution of gaseous dimethylamine and after purification by "flash" chromatography [eluent : chloroform-methanol (90-10 by volume)] and dry concentration of fractions 14 to 24 under reduced pressure (2.7 kPa) at 30 ° C, 0.8 g of dimethylamino-26 pristinamycin II _B is obtained in the form a yellow powder melting around 230 ° C.

• ₂,35 (s, 6H ^: -N(CH₃)₂)
• 3,25 (d, 1H : H 26)
• 5,05 (d, 1H : H 27)
• 8,20 (s, 1H : H 20)

NMR spectrum (CDC13 ⁺ 10% CD ₃ OD)

• _2, 35 (s, ^6H: N (CH _{3) 2)}
• 3.25 (d, 1H: H 26)
• 5.05 (d, 1H: H 27)
• 8.20 (s, 1H: H 20)

A 2% aqueous solution of dimethylamino-26 pristinamycin II _B (product BH), in the form of hydrochloride, is obtained with:

EXAMPLE 9

By operating in a manner analogous to that described in Example 1, but starting from 5.25 g of pristinamycin II _A and 5 g of methyl-4 piperazine and after purification by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume)] and dry concentration of fractions 20 to 44 under reduced pressure (2.7 kPa) at 30 ° C, 0.7 g of (4-methylpiperazinyl-1) -26 pristinamycin II is obtained _B in the form of a yellow powder melting at around 140 ° C.

• 2,30 (s, 3H : N-CH₃)
• 2,40 à 2,65 (m, 8H :
  
• 3,40 à 3,70 (m contenant H 26)
• 5,75 (d, 1H : H 27)
• 8,10 (s, 1H : H 20)

NMR spectrum:

• 2.30 (s, 3H: N-CH ₃ )
• 2.40 to 2.65 (m, 8H:
  
• 3.40 to 3.70 (m containing H 26)
• 5.75 (d, 1H: H 27)
• 8.10 (s, 1H: H 20)

A 3.3% aqueous solution of (4-methylpiperazinyl-1) -26 pristinamycin II _B (product BI) is obtained, in the hydrochloride state, with:

EXAMPLE the

A solution of 5.2 g of pristinamycin II _A in 20 cm3 of 1-methylpiperazine is stirred for 1 hour 30 minutes at a temperature in the region of 20 ° C, then is poured into 600 cm3 of distilled water. The emulsion obtained is extracted 3 times with 600 cm3 in total of methylene chloride; the organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is purified by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume)]; after dry concentration of fractions 13 to 30 under reduced pressure (2.7 kPa) at 30 ° C, 2.6 g of (4-methylpiperazinyl-1) -26 pristinamycin are obtained. They are in the form of a melting beige powder around 140 ° C.

The NMR spectrum of this product is identical to that of the product described in Example 9.

EXAMPLE 11

By following a procedure analogous to that described in Example 1, but starting with 12.6 g of pristinamycin II _A and 5.2 g of 2,3-bis-dimethylamino propanethiol and after purification by "flash" chromatography "[eluent: methylene chloride-methanol (90-10 by volume)] and dry concentration of fractions 29 to 42 under reduced pressure (2.7 kPa) at 30 ° C, 0.3 g of (bis dimethylamino) is obtained -2.3 propyl) thio-26 pristinamycin II _B in the form of a yellow powder, melting at around 110 ° C.

• 2,30 (m, 12H :
  
• 2,50 (m, 2H : -CH₂-N)
• 2,90 (m, 1H : -CH-N)
• 3,56 (m, 1H : H26)
• 4,64 (d, 1H : H27)
• 4,66 (d, 1H H27)
• 7,81 (s, 1H H20)

NMR spectrum:

• 2.30 (m, 12H:
  
• 2.50 (m, 2H: -CH ₂ -N)
• 2.90 (m, 1H: -CH-N)
• 3.56 (m, 1H: H26)
• 4.64 (d, 1H: H27)
• 4.66 (d, 1H H27)
• 7.81 (s, 1H H20)

A 2% aqueous solution of (bis 2,3-dimethylamino propyl) thio-26 pristinamycin II _B (product BJ) is obtained, in the hydrochloride state, with:

Bis-2,3-dimethylamino propanethiol can be prepared according to the method described by H. NISHIMURA and H. TAKAMATSU, Yakugaku Zasshi, 84, 944 (1964) (Chem. Abstr. 62, 2750 b (1965)).

REFERENCE EXAMPLE 1

To a solution of 0.41 cm3 of dimethylamino-3-propylamine in 15 cm3 of methanol containing 2.4 cm3 of a 2N methanolic solution of gaseous hydrochloric acid maintained at 55 ° C., 0.5 g of pristinamycin I is added _A and 20 mg of sodium cyanoborohydride. The solution obtained is then allowed to return to a temperature in the region of 20 ° C for approximately 2 hours, then it is concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is triturated with a mixture of 50 cm3 of methylene chloride and 50 cm3 of a saturated aqueous solution of sodium bicarbonate; the organic phase is decanted and the aqueous phase is extracted twice with 20 cm 3 in total of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is purified by "flash" chromatography [eluent: chloroform-methanol (80-20 by volume)]. Fractions 15 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C; the residue obtained is triturated with 5 cm3 of ethyl ether, filtered and dried under reduced pressure (0.027 kPa) at 20 ° C. 60 mg of deoxy-5γ (3-dimethylamino-propyl) amino-5y pristinamycin I _{A are} thus obtained in the form of a cream powder melting at around 160 ° C.

The full NMR spectrum has the following characteristics:

A 10% aqueous solution of deoxy-5γ (3-dimethylamino propy) amino-5γ pristinamycin I _A (product A) is obtained, in the hydrochloride state, with:

• [Les symboles ----,Z et R₁ sont définis comme en 1) pour la formule générale (V)].
  

By operating in a similar manner to that described in reference example 1, the following synergistins of general formula (V) are prepared which can be combined with the products according to the invention:

• [The symbols ----, Z and R ₁ are defined as in 1) for the general formula (V)].
  

REFERENCE EXAMPLE 8

To a solution of 2 g of pristinamycin I _A in 25 cm3 of methanol, 2.8 cm3 of a 5N ethanclic solution of dimethylamine and then 2 cm3 of a 5N methanolic solution of gaseous hydrochloric acid are added. To the solution thus obtained, 76 mg of sodium cyanoborohydride are added and then the mixture is stirred for 48 hours at a temperature in the region of 20 ° C. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is triturated with a mixture of 25 cm3 of methylene chloride and 25 cm3 of a saturated aqueous solution of sodium bicarbonate; the organic phase is decanted and the aqueous phase is extracted twice with 50 cm3 in total of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is purified by "flash" chromatography [eluent: chloroform-methanol (92-8 by volume)]. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 0.7 g of deoxy-5γ dimethylamino-5y pristinamycin I _{A is} thus obtained in the form of a beige powder, melting at around 170 ° C.

• ₀,70 (dt, 1H : 5β₂)
• 2,10 à 2,60 (m, 4H : 5δ₁ ⁺ 5⁶ ₂ ⁺ 5β₁ ⁺ 5y)
• 2,15 (s, 3H x 0,8 : -N(CH₃)₂ 1er isomère)
• 2,20 (s, 3H x 0,2 : -N(CH₃)₂ 2ème isomère)

NMR spectrum:

• _0, 70 (dt, 1H: 5β ₂₎
• 2.10 to 2.60 (m, 4H: 5δ ₁ ⁺ 5 ⁶ ₂ ⁺ 5β ₁ ⁺ 5y)
• 2.15 (s, 3H x 0.8: -N (CH ₃ ) ₂ 1st isomer)
• 2.20 (s, 3H x 0.2: -N (CH ₃ ) ₂ 2nd isomer)

an aqueous solution at 2% of 5-deoxy-5γ dimethylamino-5γ pristinamycin I _A (product B), in the form of hydrochloride, is obtained with:

REFERENCE EXAMPLE 9

By following a procedure analogous to that described in reference example 8, 0.35 g of deoxy-5y methyl-amino-5y pristinamycin I _A is obtained in the form of a yellow powder, melting at around 185 ° C.

An aqueous solution of 1% 5-deoxy-5γ methylamino-5y pristinamycin I _{A is} obtained in the hydrochloride state.

REFERENCE EXAMPLE 10

By operating in a manner analogous to that described in reference example 8, 1.2 g of deoxy-5Y [N- (2-dimethylamino ethyl) N-methylamino] -5γ pristinamycin I _A in the form of a white powder melting around 120 ° C.

A 10% aqueous solution of deoxy-5y [N- (2-dimethylamino ethyl) N-methylamino] -5y pristinamycin I _A (product D) is obtained in the hydrochloride state.

REFERENCE EXAMPLE 11

5 g of 3 A molecular sieve are added to a solution of 3 g of pristinamycin I _A , 3; 3 g of 4-diethylamino-1-methyl butylamine, 0.11 g of sodium cyanoborohydride and 9 cm 3 of a 5K methanolic solution gaseous hydrochloric acid in 75 cm3 of methanol. The suspension obtained is stirred for 4 days at a temperature in the region of 20 ° C, then is filtered; the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is triturated with a mixture of 50 cm3 of methylene chloride and 50 cm3 of a saturated aqueous solution of sodium bicarbonate: the organic phase is decanted and the aqueous phase is extracted twice with 50 cm3 of total chloride methylene. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is purified by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume)]. 0.7 g of deoxy-5γ (4-diethylamino-1-methyl-butyl) amino-5γ pristinamycin I _{A is} thus obtained in the form of a beige powder melting at around 160 ° C.

• 1,10 (mt, 9H : -N(CH₂CH₃)₂ + -CH-CH₃
• vers 1,7 (m, 4H : -CH₂-CH₂-CH₂-N(C₂H₅)₂)
• ₂,9₀ (m, 6H : -CH₂N(CH₂CH₃)₂
• 7,70 (mt, 1H x 0,45 : l'H₆ 1er isomère)
• 7,77 (mt, 1H x 0,55 : l'H₆ 2ème isomère)

NMR spectrum::

• 1.10 (mt, 9H: -N (CH ₂ CH ₃ ) ₂ + -CH-CH ₃
• around 1.7 (m, 4H: -CH ₂ -CH ₂ -CH ₂ -N (C ₂ H ₅ ) ₂ )
• ₂ , 9 ₀ (m, 6H: -CH ₂ N (CH ₂ CH ₃ ) ₂
• 7.70 (mt, 1H x 0.45: H ₆ 1st isomer)
• 7.77 (mt, 1H x 0.55: H ₆ 2nd isomer)

A 10% aqueous solution of deoxy-5y (4-diethylamino-1-methyl-butyl) amino-5γ pristinamycin I _A (product F) is obtained, in the hydrochloride state, with:

REFERENCE EXAMPLE 12

To a solution of 12.5 g of deoxy-5γ hydroxyimino-5y pristinamycin I _A in 300 cm3 of methanol containing 10 cm3 of a 2N methanolic solution of gaseous hydrochloric acid, 0.7 g of sodium cyanoborohydride is added. The solution obtained is stirred for 2 days at a temperature in the region of 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is triturated in a mixture of 200 cm3 of methylene chloride and 100 cm3 of a saturated aqueous solution of sodium bicarbonate; the organic phase is decanted and the aqueous phase is extracted with 100 cm3 of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. Obtained after purification by "flash" chromatography [eluent: chloroform-methanol (95-5 by volume)] 6.8 g of deoxy-5y hydroxyamino-5γ pristinamycin I _A in the form of a white powder melting at around 170 ° C. NMR spectrum: 0.4 (m, 1H: 5β ₂ ); 2.45 (d, 1H: 5β ₂ ); 3.1 (d: 5y in a complex massif); 7.80 (mt, 1H x 0.75: H ₆ 1st isomer); 7.95 (mt, 1H x 0.25: H ₆ 2nd isomer).

Deoxy-5y hydroxyimino-5γ pristinamycin I _A can be obtained by stirring for 5 hours at a temperature in the region of 20 ° C, 15 g of pristinamycin I _A and 7.5 g of hydroxylamine hydrochloride dissolved in 150 cm3 of methanol containing 8 cm3 of a methanoli ^q ue 2N solution of gaseous hydrochloric acid. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is triturated with a mixture of 100 cm3 of chloroform and 100 cm3 of a saturated aqueous solution of sodium bicarbonate; the organic phase is decanted and the aqueous phase is extracted twice with 200 cm3 in total of chloroform. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 14 g of deoxy-5γ hydroxyimino-5y pristinamycin IA are thus obtained in the form of a beige powder melting at 210 ° C.

• 0,35 (dd, 1H ^: 5β₂)
• 3,25 (m, 2H : 4ε₂ ⁺ 5β₁)
• 5,05 (d, 1H : 5a)
• 5,5 (m, 2H dont 5ε₁)
• 7,80 (dd, 1H x 0,40 : l'H₆ ler isomère)
• 7,90 (dd, 1H x 0,60 : l'H₆ 2ème isomère)

NMR spectrum:

• 0.35 (dd, 1H ^: 5β ₂ )
• 3.25 (m, 2H: 4ε ₂ ⁺ 5β ₁ )
• 5.05 (d, 1H: 5a)
• 5.5 (m, 2H including 5ε ₁ )
• 7.80 (dd, 1H x 0.40: H ₆ l isomer)
• 7.90 (dd, 1H x 0.60: H ₆ 2nd isomer)

REFERENCE EXAMPLE 13

By following a procedure analogous to that described in reference example 11, 0.8 g of [N- (carboxymethyl) methylamino) -5γ deoxy-5y pristinamycin I _{A is} obtained in the form of a cream powder melting around 140 ° vs.

A 2% aqueous solution of [N- (carboxymethyl) methylamino] -5γ deoxy-5y pristinamycin I _A (product K) is obtained with:

REFERENCE EXAMPLE 14

To a solution of 3.2 g of deoxy-5y (2-dimethylaminoethyl) amino-5y pristinamycin I _A in 50 cm3 of chloroform containing 0.6 cm3 of triethylamine, 0.3 cm3 of acetyl chloride is added. The reaction mixture is stirred for 30 minutes at a temperature in the region of 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is purified by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume)]; by dry concentration of fractions 10 to 21 under reduced pressure (2.7 kPa) at 30 ^c C, 1.8 g of deoxy-5y [N- (2-ethylethylamino) acetamido] -5γ p _r isti _nam ycine I _A are obtained of a white powder melting around 170 ° C.

• 0,9 (m, 4H : 2_γ ⁺ 5β₂)
• 2,05 à 2,15 (m, 3H : 5δ₁ ⁺ 56₂ + ⁵y)
• 2,15 (s, 3H : -COCH₃)
• ₂,45 (s, 6H : -N(CH₃)₂)
• 2,35 à 2,60 (m, 5H : N-CH₂-CH₂-N + 5β₁)
• 7,8 (mt, 1H x 0,75 : l'H₆ 1er isomère)
• 8,25 (mt, 1H x 0,25 : l'H₆ 2ème isomère)

NMR spectrum:

• 0.9 (m, 4H: 2 _γ ⁺ 5β ₂ )
• 2.05 to 2.15 (m, 3H: 5δ ₁ ⁺ 56 ₂ + ⁵ y)
• 2.15 (s, 3H: -COCH ₃ )
• _2, 45 (s, 6H: N (CH _{3) 2)}
• 2.35 to 2.60 (m, 5H: N-CH ₂ -CH ₂ -N + 5β ₁ )
• 7.8 (mt, 1H x 0.75: H ₆ 1st isomer)
• 8.25 (mt, 1H x 0.25: H ₆ 2nd isomer)

A 10% aqueous solution of deoxy-5γ [N- (2-dimethylamino ethyl) acetamido] -5γ pristinamycin I _A (product L) is obtained, in the hydrochloride state, with:

Deoxy-5y (2-dimethylamino ethyl) amino-5γ pristinamycin I _A can be prepared as described in Example 5.

REFERENCE EXAMPLE 15

By following a procedure analogous to that described in reference example 14, 1.6 g of deoxy-5y [N- (3-dimethylamino-propyl) acetamido] -5y pristinamycin I _{A are} obtained in the form of a powder. ocher melting at 210 ° C.

A 10% aqueous solution of deoxy-5y [N- (3-dimethylamino-propyl) acetamido] -5y pristinamycin I _A (product M) is obtained in the hydrochloride state.

REFERENCE EXAMPLE 16

To a solution of 3.6 g of methylene-5δ pristinamycin I _A in a mixture of 25 cm3 of methanol and 5 cm3 of chloroform, 1.95 g of 3-dimethylamino propanethiol is added, then the solution obtained is stirred for 20 hours at a temperature close to 20 ° C. The reaction mixture is then poured into 250 cm3 of distilled water; the emulsion obtained is extracted 3 times with 250 cm3 in total of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is purified by "flash" chromatography [eluent: chloroform-methanol (95-5 by volume)]; fractions 10 to 38 are concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is triturated in 30 cm3 of ethyl ether; the crystals obtained are separated by filtration, then dried under reduced pressure (27 Pa) at 20 ° C. 2.4 g of (dimethylamino-3 propyl) thiomethyl-56 pristinamycin 1A are thus obtained in the form of white crystals, melting at 234 ° C.

NMR spectrum:

A 10% aqueous solution of (dimethyl-3-amino-propyl) thiomethyl-56 pristinamycin I _A (product AA) is obtained, with:

• A une solution de 12 g de diméthylaminométhylène-56 pristinamycine I_A dans 230 cm3 de tétrahydrofuranne contenant 1,2 cm3 d'acide trifluoroacétique, on ajoute 0,43 g de cyanoborohydrure de sodium. La solution obtenue est agitée pendant 4 heures à une température voisine de 20°C, puis est concentrée à sec sous pression réduite (2,7 kPa) à 30°C. Le résidu obtenu est purifié par chromatographie "flash" [éluant : chloroforme-méthanol (95-5 en volumes)] ; les fractions Δ à 15 sont concentrées à sec sous pression réduite (2,7 kPa) à 30°C. On obtient ainsi 5,5 g de méthylène-5δ pristinamycine I_A sous forme de cristaux blancs fondant à 245°C.

Methylene-56 pristinamycin I _A can be prepared as follows:

• To a solution of 12 g of dimethylaminomethylene-56 pristinamycin I _A in 230 cm3 of tetrahydrofuran containing 1.2 cm3 of trifluoroacetic acid, 0.43 g of sodium cyanoborohydride is added. The solution obtained is stirred for 4 hours at a temperature in the region of 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is purified by "flash" chromatography [eluent: chloroform-methanol (95-5 by volume)]; fractions Δ to 15 are concentrated dry under reduced pressure (2.7 kPa) at 30 ° C. 5.5 g of methylene-5δ pristinamycin I _{A are} thus obtained in the form of white crystals melting at 245 ° C.

• 0,55 (dd, 1H ^{: 58} ₂)
• 2,40 (d, 1H : 5⁸ ₁)
• 3,55 (dd, 1H : 5∈₂)
• 5,25 (m, 2H : 5a +5∈₁)
• 5,30 et 6,10 (2s, 2H :
  
• 7,85 (dd, 1H : l'^H ₆)

NMR spectrum:

• 0.55 (dd, 1H ^{: 58} ₂ )
• 2.40 (d, 1H: 5 ⁸ ₁ )
• 3.55 (dd, 1H: 5∈ ₂ )
• 5.25 (m, 2H: 5a + 5∈ ₁ )
• 5.30 and 6.10 (2s, 2H:
  
• 7.85 (dd, 1H: ^H ₆ )

• A une solution de 46 g de pristinamycine I_A dans 460 cm3 de dichloro-1,2 éthane, on ajoute 230 cm3 de tert-butoxy bis(diméthylamino)méthane ; la solution obtenue est agitée pendant 18 heures à une température voisine de 20°C. Le mélange réactionnel est dilué par 1 litre de chlorure de méthylène puis lavé 3 fois par 3 litres au total d'une solution aqueuse à 0,4 % de chlorure d'ammonium. La phase organique est séchée sur du sulfate de magnésium, filtrée puis concentrée à sec sous pression réduite (2,7 kPa) à 30°C. Le résidu obtenu est trituré avec 600 cm3 d'eau distillée ; le mélange est filtré et le produit solide est séché sous pression réduite (2,7 kPa) à 20°C. On obtient 41 g de diméthylaminc- méthylène-56 pristinamycine I_A brute sous forme d'une poudre beige. Ce produit est d'une qualité suffisante pour être utilisé tel quel dans les phases ultérieures. Il peut toutefois être purifié de la manière suivante :
• 23,5 g de diméthylaminométhylène-5δ pristinam^ycine I_Abrute sont purifiés par chromatographie "flash" [éluant : chloroforme-méthanol (98-2 en volumes)]. Les fractions 16 à 25 sont réunies et concentrées à sec sous pression réduite (2,7 kPa) à 30°C. On obtient ainsi 12 g de diméthylaminométhylène-5δ pristinamycine I_A sous forme d'une poudre beige fondant vers 195°C.

Dimethylaminomethylene-5δ pristinamycin I _A can be prepared as follows:

• To a solution of 46 g of pristinamycin I _A in 460 cm3 of 1,2-dichloroethane, 230 cm3 of tert-butoxy bis (dimethylamino) methane are added; the solution obtained is stirred for 18 hours at a temperature in the region of 20 ° C. The reaction mixture is diluted with 1 liter of methylene chloride and then washed 3 times with 3 liters in total of an aqueous solution at 0.4% of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is triturated with 600 cm3 of distilled water; the mixture is filtered and the solid product is dried under reduced pressure (2.7 kPa) at 20 ° C. 41 g of crude dimethylaminc-56-methylene pristinamycin I _{A are} obtained in the form of a beige powder. This product is of sufficient quality to be used as is in subsequent phases. However, it can be purified as follows:
• 23.5 g of dimethylaminomethylene-5δ pristinam ^and cine I _A crude are purified by "flash" chromatography [eluent: chloroform-methanol (98-2 by volume)]. Fractions 16 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 12 g of dimethylaminomethylene-5δ pristinamycin I _{A are} thus obtained in the form of a beige powder melting at around 195 ° C.

• 0,9 (t, 3H : 2Y)
• 1,₀ (dd, 1H 5ß₂)
• 2,50 (d, 1H : 5ß₁)
• 3,1₀ (s, 6H : -N(CH₃)₂)
• ₃,_{70 (d}, 1H 5∈₂)
• 5,50 (d, 1H : 5∈₁)
• ₇,_{40 (s}, 1H : =CHN(CH₃)₂)
• 7,75 (dd, 1H : l'^H ₆)

NMR spectrum:

• 0.9 (t, 3H: 2Y)
• 1, ₀ (dd, 1H 5ß ₂ )
• 2.50 (d, 1H: 5ß ₁ )
• 3.1 ₀ (s, 6H: -N (CH ₃ ) ₂ )
• _{3, 70 (d,} 1H 5∈ ₂₎
• 5.50 (d, 1H: 5∈ ₁ )
• _{7, 40 (s,} 1H: = CHN (CH _{3) 2)}
• 7.75 (dd, 1H: ^H ₆ )

REFERENCE EXAMPLE 17

By operating in a manner analogous to that described in reference example 16, but starting from 0.9 g of 5-methylene-virginiamycin S and 0.52 g of 3-dimethylamino propanethiol and after purification by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume)] and dry concentration of fractions 13 to 25 under reduced pressure (2.7 kPa) at 30 ° C, 0.3 g of (3-dimethylamino propyl) is obtained thiomethyl-5δ virginiamycin S in the form of a white powder melting around 142 ° C.

• ₀,45 (dd, 1H 5ß₂)
• 1,90 (m, 2H : -SCH₂CH₂CH₂N〈)
• 2,40 (s, 6H :
  
• 2,60 (m, 4H : -S-CH₂-CH₂-CH₂-N〈)
• 3,45 (d, 1H : 5∈₂)
• 4,85 (m, 3H dont 5ε₁)
• 5,25 (dd, 1H : 5a)
• 7,78 (dd, 1H : l'^H ₆)

NMR spectrum:

• _0.45 (dd, 1H 5ß ₂ )
• 1.90 (m, 2H: -SCH ₂ CH ₂ CH ₂ N 〈)
• 2.40 (s, 6H:
  
• 2.60 (m, 4H: -S-CH ₂ -CH ₂ -CH ₂ -N 〈)
• 3.45 (d, 1H: 5∈ ₂ )
• 4.85 (m, 3H including 5ε ₁ )
• 5.25 (dd, 1H: 5a)
• 7.78 (dd, 1H: ^H ₆ )

A 10% aqueous solution of (3-dimethylamino propyl) thiomethyl-5δ virginiamycin S (product AB), in the form of hydrochloride, is obtained with:

Methylene-5δ virginiamycin S can be prepared in a manner analogous to that described in Example / 16 for methylene-56 pristinamycin I _A , but from 2 g of dimethylaminomethylene-5δ virginiamycin S and 74 mg sodium cyanoborohydride. After purification by "flash" chromatography [eluent: chloroform-methanol (98-2 by volume)] and dry concentration of fractions 2 to 5 under reduced pressure (2.7 kPa) at 30 ° C, 1 g of methylene is obtained -5δ virginiamycin S in the form of a beige powder, melting around 190 ° C.

• ₀,35 (dd, 1H: 5β₂)
• ₂,45 (dd, 1H ^: 5β₁)
• 3,55 (dd, 1H ^{: 5£} ₂)
• 5,25 (dd, 1H : 5ε₁)
• 5,25 (m, 1H : 5a)
• 5,30 et 6,15 (2s, 2H :
  
• 7,75 (dd, 1H : l'^H ₆)

RMS spectrum:

• _0, 35 (dd, 1H: 5β ₂₎
• _2, 45 (dd, ^1H: ₁ 5β)
• 3.55 (dd, 1H ^{: 5 £} ₂ )
• 5.25 (dd, 1H: 5ε ₁ )
• 5.25 (m, 1H: 5a)
• 5.30 and 6.15 (2s, 2H:
  
• 7.75 (dd, 1H: ^H ₆ )

Dimethylaminomethylene-5δ virginiamycin S can be obtained by operating in a manner analogous to that described in reference example 16 for dimethylaminomethylene-5δ pristinamycin I _A , but from 2 g of virginiamycin S and 10 cm 3 of bis- dimethylamino tert-butoxymethane and after purification by "flash" chromatography [eluent: chloroform-methanol (98-2 by volume)] and dry concentration of fractions 9 to 12 under reduced pressure (2.7 kPa) at 30 ° C, obtains 0.8 g of dimethylaminomethylene-5δ virginiamycin S in the form of a yellow powder melting at 175 ° C.

• 0,9 (m, 4H : 2γ+ 5β₂)
• ₃,₀5 (s, 6H : =CH-N(CH₃)₂)
• 3,65 (d, 1H : 5ε₂)
• 4,85 (d, 1H ^: 5ε₁)
• 5,15 (dd, 1H : 5a)
• 7,10 à 7,40 (m : aromatiques + =CH-N〈)
• 7,70 (dd, 1H : l'H₆)

NMR spectrum:

• 0.9 (m, 4H: 2γ + 5β ₂ )
• ₃ , ₀ 5 (s, 6H: = CH-N (CH ₃ ) ₂ )
• 3.65 (d, 1H: 5ε ₂ )
• 4.85 (d, 1H ^: 5ε ₁ )
• 5.15 (dd, 1H: 5a)
• 7.10 to 7.40 (m: aromatics + = CH-N 〈)
• 7.70 (dd, 1H: H ₆ )

REFERENCE EXAMPLE 18

By operating in a manner analogous to that described in reference example 16, but using 6 g of methylene-5δ pristinamycin I _A and 4 cm3 of (methyl-4 piperazinyl-1) -2 ethanethiol and after purification by "flash" chromatography [eluent: chloroform-methanol (97-3 by volume)] and dry concentration of fractions 8 to 20 under reduced pressure (2.7 kPa) at 30 ° C, 2.6 g of [( 4-methyl-piperazinyl-1) -2 ethyl] thiomethyl-56 pristinamycin I _A in the form of white crystals, melting at 216 ° C.

• ₀,60 (dd, 1H ^: 5β₂)
• 2,27 (s, 3H : N-CH₃)
• 2,40 à 2,80 (m, 11H :
  
• 5,05 (dd, 1H ^: 5ε₁)
• 5,27 (m, 2H : 5a + 4a)
• 7,85 (mt, 1H x 0,8 : l'H₆ 1er isomère)
• 7,95 (mt, 1H x 0,2 : l'H₆ 2ème isomère)

NMR spectrum:

• _0, 60 (dd, ^1H: 5β ₂₎
• 2.27 (s, 3H: N-CH ₃ )
• 2.40 to 2.80 (m, 11H:
  
• 5.05 (dd, 1H ^: 5ε ₁ )
• 5.27 (m, 2H: 5a + 4a)
• 7.85 (mt, 1H x 0.8: H ₆ 1st isomer)
• 7.95 (mt, 1H x 0.2: H ₆ 2nd isomer)

A 5% aqueous solution of [(4-imethyl-1-piperazinyl) -2 ethyl] thiomethyl-56 pristinamycin I _A (product AC, as hydrochloride, with:

REFERENCE EXAMPLE 19

By operating in a manner analogous to that described in reference example 16, but using 2 g of methylene-5δ pristinamycin I _A and 3 cm3 of (methyl-4 piperazinyl-1) -3 propanethiol and after purification by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume)] and dry concentration of fractions 10 to 25 under reduced pressure (2.7 kPa) at 30 ° C, 1.9 g of [( 4-methyl-piperazinyl-1) -3 propyl] thiomethyl-5δ pristinamycin I _A in the form of a white powder melting around 156 ° C.

• ₀,65 (dd, 1H ^: 5β₂)
• 2,30 (s, 3H : N-CH₃)
• 2,50 (m, 13H :
  
  +-sCH^- ₂ + 5β₁)
• 5,27 (m, 2H : 5a + 4α)
• 7,85 (dd, 1H x 0,8 : l'H₆ 1er isomère)
• 7,95 (dd, 1H x 0,2 : l'H₆ 2ème isomère)

NMR spectrum:

• _0, 65 (dd, ^1H: 5β ₂₎
• 2.30 (s, 3H: N-CH ₃ )
• 2.50 (m, 1 p.m .:
  
  + -sCH ^- ₂ + 5β ₁ )
• 5.27 (m, 2H: 5a + 4α)
• 7.85 (dd, 1H x 0.8: H ₆ 1st isomer)
• 7.95 (dd, 1H x 0.2: H ₆ 2nd isomer)

A 10% aqueous solution of [(methyl-4 piperazinyl-1) -3 propyl] thiomethyl-5δ pristinamycin I _A (product AD) is obtained, in the hydrochloride state, with:

REFERENCE SAMPLE 20

By following a procedure analogous to that described in reference example 16, but using 4 g of methylene-5δ pristinamycin I _A and 4 cm3 of 1,3-dimethylamino-propanethiol-2 and after purification by "flash" chromatography [eluting. chloroform-methanol (95-5 by volume)] and dry concentration of fractions 20 to 60 under reduced pressure (2.7 kPa) at 30 ° C, 0.59 g of [bis (dimethylamino) -1.3 is obtained propyl-2] thiomethyl-5δ pristinamycin I _A in the form of a white powder melting at around 170 ° C.

• ₀,63 (dd, 1H : 5β₂)
• 2,40 (s, 6H : -N(CH₃)₂)
• 2,50 (m, 10H :
  
  + -N(CH₃)₂)
• 4,97 (s, 1H : 5ε₁)
• 5,30 (m, 2H : 5α + 4α)
• 7,85 (mt, 1H x 0,85 : l'H₆ ler isomère)
• 7,95 (mt, 1H ^x 0,15 : 1'H₆ 2ème isomère)

NMR spectrum:

• _0, 63 (dd, 1H: 5β ₂₎
• 2.40 (s, 6H: -N (CH ₃ ) ₂ )
• 2.50 (m, 10H:
  
  + -N (CH ₃ ) ₂ )
• 4.97 (s, 1H: 5ε ₁ )
• 5.30 (m, 2H: 5α + 4α)
• 7.85 (mt, 1H x 0.85: H ₆ l isomer)
• 7.95 (mt, 1H ^x 0.15: 1'H ₆ 2nd isomer)

A 7.5% aqueous solution of bis [(dimethylamino) -1.3 propyl-2] thiomethyl-S ^O pristinamycin I _A (product AE) is obtained, in the hydrochloride state, with:

REFERENCE EXAMPLE 21

By operating in a manner analogous to that described in reference example 16, but using 3 g of methylene-5δ pristinamycin I _A and 0.97 g of methyl-1 mercapto-4 piperidine and after purification by chromatography " flash "[eluent: chloroform-methanol (95-5 by volume)] and dry concentration of fractions 10 to 16 under reduced pressure (2.7 kPa) at 30 ° C, 1.1 g of (methyl-1 piperidyl-4) thiomethyl-5δ pristinamycin I _A in the form of a white powder melting at 260 ° C.

• ₀,6 (dd, 1H ^: 5β₂)
• 2 (m, 4H : -S-.
  
• 2,20 (s, 3H :
  
• 2,35 (m, 1H ^: 5β₁)
• 2,90 (m, 4H :
  
• 5,30 (m, 2H : 5α + 4α)
• 7,85 (dd, 1H : l'H₆)

NMR spectrum:

• ₀ , 6 (dd, 1H ^: 5β ₂ )
• 2 (m, 4H: -S-.
  
• 2.20 (s, 3H:
  
• 2.35 (m, 1H ^: 5β ₁ )
• 2.90 (m, 4H:
  
• 5.30 (m, 2H: 5α + 4α)
• 7.85 (dd, 1H: H ₆ )

A 5% aqueous solution of (methyl-1 piperidyl-4) thiomethyl-5δ pristinamycin I _A (product AF), in the form of hydrochloride, is obtained with:

REFERENCE EXAMPLE 22

By operating as in reference example 16 but using 2 g of methylene-5δ pristinamycin I _A and 0.66 g of diethylamino-2 ethanethiol, one obtains after purification by "flash" chromatography [eluent: chloroform-methanol (95-5 by volume)] and dry concentration of fractions 9 to 18 under reduced pressure (2.7 kPa) at 30 ° C, 0.8 g of (2-ethyl diethylamino) thiomethyl-56 pristinamycin I _A in the form a beige powder melting at 230 ° C.

• 0,65 (dd, 1H : 5β₂)
• 2,38 (d, 1H : 5β₁)
• 2,3 à 2,8 (m, 8H : -S CH₂CH₂
  
• 3,15 (dd, 1H : -CH₂S-)
• 3,35 (dd, 1H : -CH₂S-)
• 5,01 (dd, 1H : 5ε₁)
• 7,81 (dd, 1H x 0,9 : l'H₆ 1er isomère)
• 7,90 (dd, 1H x 0,1 : l'H₆ 2ème isomère)

NMR spectrum:

• 0.65 (dd, 1H: 5β ₂ )
• 2.38 (d, 1H: 5β ₁ )
• 2.3 to 2.8 (m, 8H: -S CH ₂ CH ₂
  
• 3.15 (dd, 1H: -CH ₂ S-)
• 3.35 (dd, 1H: -CH ₂ S-)
• 5.01 (dd, 1H: 5ε ₁ )
• 7.81 (dd, 1H x 0.9: H ₆ 1st isomer)
• 7.90 (dd, 1H x 0.1: H ₆ 2nd isomer)

A 5% aqueous solution of (2-ethyl diethylamino) thiomethyl-56 pristinamycin I _A (product AF ₁ ) is obtained in the hydrochloride form, with:

REFERENCE EXAMPLE 23

To a solution of 5.5 g of dimethylaminomethylene-5δ pristinamycin I _A in 60 cm3 of acetic acid is added dropwise 5.3 g of 2-dimethylaminoethylamine so as not to exceed 25 ° C. The solution obtained is stirred for 20 hours at a temperature in the region of 20 ° C., then is poured slowly into a saturated aqueous solution of sodium bicarbonate; the mixture obtained is extracted twice with 750 cm3 in total of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is purified by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume)] .; fractions 10 to 12 are concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 3 g of (dimethylamino-2 ethyl) aminomethylene-56 pristinamvcine I _{A are} thus obtained in the form of a beige powder melting at around 180 ° C.

• ₀,₉₀ (mt, 4H : 2Y + 5β₂)
• ₂,25 (mt, 6H : -N(CH₃)₂)
• 2,50 (mt, 3H : - CH₂N〈 ⁺ 5β₁)
• 3,25 (mt, 2H : -N-CH₂-)
• 3,50 (mt, 2H ^: 5ε₂ ⁺ 3δ₁)
• 4,90 (mt, 1H: 5ε₁)
• entre 7,15 et 7,4 (m, 1H :
  
• 9,90 (mt, 1H (échangeable D20): -NH-)

NMR spectrum:

• ₀ , ₉₀ (mt, 4H: 2Y + 5β ₂ )
• _2, 25 (mt, 6H: -N (CH _{3) 2)}
• 2.50 (mt, 3H: - CH ₂ N 〈 ⁺ 5β ₁ )
• 3.25 (mt, 2H: -N-CH ₂ -)
• 3.50 (mt, 2H ^: 5ε ₂ ⁺ 3δ ₁ )
• 4.90 (mt, 1H: 5ε ₁ )
• between 7.15 and 7.4 (m, 1H:
  
• 9.90 (mt, 1H (exchangeable D20): -NH-)

A 1% aqueous solution of (2-dimethylaminoethyl) aminomethylene-56 pristinamycin I _A (product AG) is obtained, with:

REFERENCE EXAMPLE 24

By operating in a manner analogous to that described in reference example 23, but starting from 13.8 g of dimethylaminomethylene-56 pristinamycin I _A and 3.4 g of 4-amino-1-methyl-piperidine and after purification by "flash" chromatography [eluent: chloroform-methanol (92.5-7.5 by volume)] and dry concentration of fractions 15 to 20 under reduced pressure (2.7 kPa) at 30 ° C, 4 are obtained, 0 g of (methyl-1 piperidyl-4) aminomethylene-5δ pristinamycin I _A in the form of a yellow powder melting at 208 ° C.

• 0,40 (m, 4H : 2_Y ⁺ 2β₂)
• 2,0 (m, 4H :
  
• 2,35 (s, 3H : N-CH₃)
• 2,45 (d, 1H : 5β₁)
• 2,90
  
• 3,20 (sous un massif, 1H :
  
• 3,50 (d, 1H : 5ε₂)
• 4,85 (sous un massif, 1H : 5ε₁)
• 6,65 (d, 1H : =CHNH-)
• 9,70 (dd, 1H x 0,15 : =CH-NH- 1er isomère)
• 10,03 (dd, 1H x 0,85 : =CH-NH- 2ème isomère)

NMR spectrum:

• 0.40 (m, 4H: 2 _Y ⁺ 2β ₂ )
• 2.0 (m, 4H:
  
• 2.35 (s, 3H: N-CH ₃ )
• 2.45 (d, 1H: 5β ₁ )
• 2.90
  
• 3.20 (under a massif, 1H:
  
• 3.50 (d, 1H: 5ε ₂ )
• 4.85 (under a bed, 1H: 5ε ₁ )
• 6.65 (d, 1H: = CHNH-)
• 9.70 (dd, 1H x 0.15: = CH-NH- 1st isomer)
• 10.03 (dd, 1H x 0.85: = CH-NH- 2nd isomer)

A 10% aqueous solution of (methyl-1 piperidyl-4) aminomethylene-56 pristinamycin I _A (product AT), in the form of hydrochloride, is obtained with:

The amino-4 methyl-1 piperidine can be prepared by the method described by E.F. ELSLAGER, L.M. WERBEL, A. CURRY, N. HEADEN, J. JOHNSON, J. Med. Chem. 17, 99 (1974).

By operating as in reference example 23, the synergistins of general formula (V) below are prepared, which can be combined with the products according to the invention.

[The symbols ------, X and Z are defined as in 2b) for the general formula (V) and, unless special mention, Y represents a dimethylamino radical].

REFERENCE EXAMPLE 40

To a solution of 1.84 g of dimethylarinomethylene-5δ pristinamycin I _A in 40 cm3 of acetic acid, 2.1 g of 2-dimethylaminoethanethiol is added. The solution obtained is stirred for 20 hours at a temperature in the region of 20 ° C, then is poured slowly into a saturated aqueous solution of sodium bicarbonate; the mixture obtained is extracted 3 times with 400 cm3 in total of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is purified by "flash" chromatography [eluent: chloroform-methanol (96-4 by volume)]; fractions 5 and 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 0.8 g of (2-dimethylamino-ethyl) thiomethylene-5d pristinamycin I _{A is} thus obtained in the form of a yellow powder melting at around 150 ° C.

• 0,68 (dd, 1H : 5β₂)
• ₂,₃₂ (_s, _{6H x 0},_{85 :} -CH₂N(CH₃)₂ 1er isomère)
• 2,35 (s, 6H x 0,15 : -CH₂N(CH₃)₂ 2ème isomère)
• ₂,45 (d, 1H ^: 5β₁)
• 2,65 (mt, 2H : -SCH₂-)
• 3,05 (t, 2H : -CH₂N〈)
• 3,43 (dd, 1H : 5ε₂)
• 5,15 (dans un massif : 5ε₁)
• 7,60 (s large, 1H : =CHS-)
• 7,83 (mt, 1H : l'H₆ deux isomères)

NMR spectrum:

• 0.68 (dd, 1H: 5β ₂ )
• ₂ , ₃₂ ( _s , _{6H x 0.85 :} -CH ₂ N (CH ₃ ) ₂ 1st isomer)
• 2.35 (s, 6H x 0.15: -CH ₂ N (CH ₃ ) ₂ 2nd isomer)
• _2, 45 (d, ^1H: ₁ 5β)
• 2.65 (mt, 2H: -SCH ₂ -)
• 3.05 (t, 2H: -CH ₂ N 〈)
• 3.43 (dd, 1H: 5ε ₂ )
• 5.15 (in a massif: 5ε ₁ )
• 7.60 (wide s, 1H: = CHS-)
• 7.83 (mt, 1H: H ₆ two isomers)

A 1% aqueous solution of (2-dimethylamino ethyl) thiomethylene-5δ pristinamycin I _{A (} product AX), in the form of hydrochloride, is obtained with:

By operating as in reference example 40, the following synergistins of general formula (V) are prepared, which can be combined with the products according to the invention. [The symbols ----, X and Z are defined as in 2b) for the general formula (V) and, unless special mention, Y represents a dimethylamino radical].

REFERENCE EXAMPLE 56

To a solution of 0.87 g of (2-mercapto-propyl) -1 4-methyl-piperazine in 50 cm3 of ethanol supplemented with 0.34 g of sodium ethylate, a solution of 5.2 g of ( 4-methylphenyl) sulfonyloxymethylene-5δ pristinamycin I _A in 50 cm3 of methylene chloride. The reaction mixture is stirred for 16 hours at a temperature in the region of 20 ° C. and then diluted with 500 cm3 of methylene chloride and 100 cm3 of distilled water. After stirring, the aqueous phase is extracted twice with 50 cm3 of methylene chloride in total. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is purified by "flash" chromatography [eluent: chloroform-methanol (97.5-2.5 by volume)]. Fractions 33 to 80 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 1.25 g of [(methyl-4 piperazinyl-1) -3-propyl-2] thiomethylene-56 pristinamycin I _{A are} thus obtained in the form of a beige powder melting at around 195 ° C.

• 0,70 (dd, 1H : 5⁶ ₂)
• 1,25 (d, 3H : -CH₁-CH₃)
• ₂,3₀ (s, 3H : N-CH₃)
• 2,50 (m, 10H :
  
• 3,40 (dd, 1H : 5ε₂)
• 7,85 (dd large, 1H : 1'H₆)

NMR spectrum:

• 0.70 (dd, 1H: 5 ⁶ ₂ )
• 1.25 (d, 3H: -CH ₁ -CH ₃ )
• ₂ , 3 ₀ (s, 3H: N-CH ₃ )
• 2.50 (m, 10H:
  
• 3.40 (dd, 1H: 5ε ₂ )
• 7.85 (dd large, 1H: 1'H ₆ )

A 10% aqueous solution of [(methyl-4 piperazinyl-1) -3 propyl-2] thiomethylene-5δ pristinamycin I _A (AAN product) is obtained in the form of the hydrochloride, with:

(2-Nercapto-propyl) -1 methyl-4 piperazine is prepared by heating at 100 ° C for 16 hours a mixture of 19 cm3 of propylene sulfide and 29 cm3 of N-methylpiperazine. This gives 32 g of a colorless oil distilling at 105 ° C at 1.3 kPa.

• A une solution de 2,7 g d'hydroxyméthylène-5δ pristinamycine I_A dans 30 cm3 de chlorure de méthylène, on ajoute à une température voisine de -30°C, 0,42 cm3 de triéthylamine puis 0,57 g de chlorure de l'acide p-toluènesulfonique. Le mélange réactionnel est agité ensuite pendant 2 heures à une température voisine de 20°C, puis concentré à sec sous pression réduite (2,7 kPa) à 30°C ; le résidu obtenu est purifié par chromatographie "flash" [éluant . chlorure de méthylène-méthanol (96-4 en volumes)]. Après concentration à sec des fractions 4 à 6 sous pression réduite (2,7 kPa) à 30°C, on obtient 2,2 g de (méthyl-4 phényl) sulfonyloxvméthylène-5δ pristinamycine I_A sous forme d'une poudre blanche fondant vers 265°C.

The (4-methylphenyl) sulfonyloxymethylene-5δ pristinamycin I _A can be obtained in the following manner:

• To a solution of 2.7 g of 5ym hydroxymethylene pristinamycin I _A in 30 cm3 of methylene chloride, 0.42 cm3 of triethylamine and then 0.57 g of chloride of chloride are added at a temperature in the region of -30 ° C. p-toluenesulfonic acid. The reaction mixture is then stirred for 2 hours at a temperature in the region of 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C; the residue obtained is purified by "flash" chromatography [eluent. methylene chloride-methanol (96-4 by volume)]. After dry concentration of fractions 4 to 6 under reduced pressure (2.7 kPa) at 30 ° C, 2.2 g of (4-methylphenyl) sulfonyloxvmethylene-5δ pristinamycin I _A are obtained in the form of a white fondant powder around 265 ° C.

• ₀,5₀ (dd, 1H : 5β₂)
• 2,35 (s, 3H :
  
• 3,30 (dd, 1H ^: 5ε₂)
• 5,25 (d, 1H : 5α)
• 5,30 (dd, 1H ^: 5ε₁)
• 7,35 à 7,90 (système AB + m, SH : 4δ+ 4ε +
  
• 7,85 (dd, 1H : l'H₆)

NMR spectrum:

• ₀ , 5 ₀ (dd, 1H: 5β ₂ )
• 2.35 (s, 3H:
  
• 3.30 (dd, 1H ^: 5ε ₂ )
• 5.25 (d, 1H: 5α)
• 5.30 (dd, 1H ^: 5ε ₁ )
• 7.35 to 7.90 (AB + m system, SH: 4δ + 4ε +
  
• 7.85 (dd, 1H: H ₆ )

• A 420 cm3 d'une solution aqueuse 0,1N d'acide chlorhydrique, on ajoute sous agitation 10,6 g de diméthylaminométhalène-5δ pristinamycine I_A. La solution obtenue est ensuite agitée pendant 3 heures à une température voisine de 20°C. On ajoute alors goutte à goutte 30 cm3 d'une solution aqueuse saturée de bicarbonate de sodium de manière à obtenir un pH voisin de 4. Le produit qui précipite est séparé par filtration puis lavé 3 fois par 30 cm₃ au total d'eau distillée. Après séchage sous pression réduite (2,7 kPa) à une température voisine de 20°C, on obtient 9,5 g d'hydroxyméthylène-5δ pristinamycine I_A sous forme d'une poudre beige. Ce produit est d'une qualité suffisante pour être utilisé tel quel dans les phases ultérieures. Il peut toutefois être purifié de la manière suivante :
• 9,5 g d'hydroxyméthylène-56 pristinamycine I_A brute sont dissous dans 50 cm3 d'acétate d'éthyle ; la solution obtenue est versée sur 100 g de gel de silice contenus dans une colonne de 2,8 cm de diamètre. On élue d'abord avec 400 cm3 d'acétate d'éthyle et élimine l'éluat correspondant ; on élue ensuite avec 1600 cm3 d'acétate d'éthyle et concentre l'éluat correspondant à sec sous pression réduite (2,7 kPa) à 30°C. On obtient ainsi 6,3 g d'hydroxy- méthylène-56 pristinamycine I_A sous forme de cristaux blancs fondant à 220°C.

Hydroxymethylene-56 pristinamycin I _A can be prepared as follows:

• At 420 cm3 of an 0.1N aqueous hydrochloric acid solution, 10.6 g of dimethylaminomethalene-5δ pristinamycin I _A are added with stirring. The solution obtained is then stirred for 3 hours at a temperature in the region of 20 ° C. 30 cm3 of a saturated aqueous sodium bicarbonate solution are then added dropwise so as to obtain a pH close to 4. The product which precipitates is separated by filtration and then washed 3 times with 30 cm ₃ in total of distilled water . After drying under reduced pressure (2.7 kPa) at a temperature in the region of 20 ° C, 9.5 g of 5-hydroxymethylene pristinamycin I _A is obtained in the form of a beige powder. This product is of sufficient quality to be used as is in subsequent phases. However, it can be purified as follows:
• 9.5 g of crude hydroxymethylene-56 pristinamycin I _A are dissolved in 50 cm3 of ethyl acetate; the solution obtained is poured onto 100 g of silica gel contained in a column 2.8 cm in diameter. First eluted with 400 cm3 of ethyl acetate and the corresponding eluate is removed; then eluted with 1600 cm3 of ethyl acetate and the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 6.3 g of hydroxy-methylene-56 pristinamycin I _{A are} thus obtained in the form of white crystals melting at 220 ° C.

• C:69 (dd, 1H : 5β₂)
• ₂,43 (d, 1^{H :} 5β₁)
• 3,40 (d, 1H ^: 5ε₂)
• 4,0 à 4,2 (m, 3H : 4α + 5ε₁ + 5α)
• 8,15 (s, 1H : =CH-OH)
• 11,63 (s large, 1H : =CH-OH)

NMR spectrum:

• C: 69 (dd, 1H: 5β ₂ )
• ₂ , 43 (d, 1 ^H: 5β ₁ )
• 3.40 (d, 1H ^: 5ε ₂ )
• 4.0 to 4.2 (m, 3H: 4α + 5ε ₁ + 5α)
• 8.15 (s, 1H: = CH-OH)
• 11.63 (broad s, 1H: = CH-OH)

REFERENCE EXAMPLE 57

By following a procedure analogous to that described in reference example 56, 1 g of (3-dimethylamino-2-propyl) thiomethylene-56 pristinamycin I _A is obtained in the form of a yellow powder melting at 172 ° C.

A 5% aqueous solution of (3-dimethylamino-2-propyl) thiomethylene-56 pristinamycin I _A (product AAO) is obtained in the hydrochloride state.

REFERENCE EXAMPLE 58

By following a procedure analogous to that described in reference example 56, 1.32 g of (5-diethylamino-pentyl-2) thiomethylene-56 pristinamycin I _A are obtained in the form of a beige powder melting at about 185 ° vs.

A 10% aqueous solution of (5-diethylamino-pentyl-2) thiomethylene-56 pristinamycin I _A (AAP product) is obtained in the form of the hydrochloride.

REFERENCE EXAMPLE 59

A solution of 7.6 g of [(4-methylphenyl) sulfonyloxy-methylene] -5δ pristinamycin I _A in 60 cm3 of tetrahydrofuran is cooled to a temperature in the region of -10 ° C. Is added slowly while maintaining this temperature a solution of 0.65 g of 2-dimethylamino ethanol in 60 cm3 of tetrahydrofuran supplemented with 0.35 g of a dispersion at 50% sodium hydride in mineral oil. At the end of the addition, the temperature is allowed to slowly rise to around 20 ° C. The reaction mixture is stirred for 24 hours at this temperature then diluted with 500 cm3 of methylene chloride and washed twice with 50 cm3 of a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ^c C. The residue obtained is purified by "flash" chromatography [eluent: chloroform-methanol (95-5 in volumes)]. Fractions 12 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 25 ° C. 1.5 g of (2-dimethylamino ethoxymethylene) -5δ pristinamycin I _{A are thus} obtained in the form of a beige powder melting at around 160 ° C.

• ₀,65 (dd, 1H : 5^E ₂)
• ₂,3 (s, 6H : -N(CH₃)₂)
• 2,65 (m, 2H : -CH₂N〈)
• 3,42 (dd, 1H : 5ε₂)
• 4,15 (t, 2H : -OCH₂-)
• 5,15 (d, 1H : 5ε₁)
• 7,45 (sous les aromatiques, 1H : C=CHO-)
• 7,80 (dd, 1H : l'^H ₆)

NMR spectrum:

• _0, 65 (dd, 1H: 5 ^E ₂₎
• ₂ , 3 (s, 6H: -N (CH ₃ ) ₂ )
• 2.65 (m, 2H: -CH ₂ N 〈)
• 3.42 (dd, 1H: 5ε ₂ )
• 4.15 (t, 2H: -OCH ₂ -)
• 5.15 (d, 1H: 5ε ₁ )
• 7.45 (under the aromatics, 1H: C = CHO-)
• 7.80 (dd, 1H: ^H ₆ )

A 1% aqueous solution of (2-dimethylamino ethoxymethylene) -5δ pristinamycin I _A (product AAQ) is obtained, in the form of the hydrochloride, with:

The present invention also relates to medicaments consisting of a product of general formula (I), in free form or preferably in the form of an addition salt with a pharmaceutically acceptable acid in the form of a combination with known synergistins or preferably with synergistins of general formula (V), the combination can also contain any other pharmaceutically compatible, inert or physiologically active product. The medicaments according to the invention can be used parenterally, orally, rectally or topically.

The sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, can be used. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared under form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.

As solid compositions for oral administration can be used tablets, pills, pouares or granules. In these compositions, the active product according to the invention (optionally combined with another pharmaceutically compatible product) is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.

The compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, ointments, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the products according to the invention associated with known synergistins or preferably with synergistins of general formula (V), are particularly useful in the treatment of infections of microbial origin. The doses depend on the desired effect and on the duration of the treatment; for an adult, they are generally between 500 and 2000 mg per day by the parenteral route, particularly by the intravenous route in slow infusion, the dose of synergistin of general formula (V) being itself between 500 and 2000 mg per day.

In general, the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.

The following examples, given without limitation, illustrate compositions according to the invention.

Example A

An injectable solution for infusion containing 5 g / l of active mixture having the following composition is prepared, according to the usual technique.

Example B

A solution for injection for infusion is prepared containing 1 g / 1 of active mixture having the following composition:

Claims (3)

1 - New derivative of pristinamycin II _B , characterized in that it corresponds to the general formula:

in which R represents - or a substituted alkylthio radical: - i) by one or two alkylamino or dialkoylamino radicals, the alkyl parts of which may optionally form, together with the nitrogen atom to which they are linked, a saturated heterocycle chosen from pyrrolidinyl-1, piperidino, azetidinyl-1, azepinyl-1, morpholino , thiomorpholino and piperazinyl-1 (optionally substituted by an alkyl radical), or else ii) by a pyrrolidinyl-2 or 3, piperidyl-2, 3 or 4, azetidinyl-2 or 3 or azeepinyl-2, 3 or 4 radical, - either a radical of general formula:

in which Het represents a pyrrolidinyl-3 piperidyl-3 or 4, azetidinyl-3 or azeepinyl-3 or 4 radical (optionally substituted on the nitrogen atom by an alkyl radical) - or a dialkoylamino radical, the alkyl parts of which may optionally form, together with the nitrogen atom to which they are linked, a saturated heterocycle chosen from pyrrolidinyl-1, piperidino, azetidinyl-1, azepinyl-1, morpholino, thiomorpholino and piperazinyl-1 (optionally substituted by an alkyl radical), it being understood that the radicals and alkyl portions mentioned above contain 1 to 5 carbon atoms in a straight or branched chain, where appropriate in its isomeric forms and their mixtures, as well as its salts addition with acids, pharmaceutically acceptable. 2 - Process for the preparation of a new pristinamycin derivative They according to claim 1, characterized in that a product of general formula is reacted:

in which R is defined as in claim 1 on pristinamycin II _A of formula:

then, where appropriate, separates the isomers from the product obtained and optionally transforms it into an addition salt with an acid, which is pharmaceutically acceptable. 3 - Pharmaceutical composition characterized in that it contains at least one derivative according to claim 1 associated with a known sysnergistin or a soluble synergistin of general formula:

in which Y represents a hydrogen atom or a dimethylamino radical and 1) or ----- represents a single bond, Z and R ₁ represent a hydrogen atom and X represents a radical of general formula:

in which : - either R ₂ represents a hydrogen atom and R ₃ represents a hydroxy or alkyl radical optionally substituted by a carboxy, alkyloxycarbonyl, hydroxy, alkylamino or dialkoylamino radical in which the alkyl radicals can form with the nitrogen atom to which they are attached a 4- to 7-membered heterocycle chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl or azepinyl, or else R ₃ represents a cycloalkyl radical containing 3 to 7 carbon atoms or a saturated 4 to 7-membered heterocycle chosen from azetidine, pyrrolidine, piperidine and azepine rings, these heterocycles possibly being substituted on the nitrogen atom by an alkyl radical, - either R ₂ represents a formyl or alkylcarbonyl radical and R ₃ represents an alkyl radical substituted by a carboxy, alkylamino or dialkoylamino radical in which the alkyl radicals can form with the nitrogen atom to which they are attached to a 4- to 7-membered heterocycle chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl or azepinyl, or Bien R ₃ represents a 4- to 7-membered heterocycle chosen from the azetidine, pyrrolidine, piperidine and azepine rings, these heterocycles being able to be substituted on the atom d 'nitrogen by an alkyl radical, - either R ₂ and R ₃ , identical or different, represent an alkyl radical optionally substituted by a carboxy, alkyloxycarbonyl, hydroxy, alkylamino or dialkoylamino radical in which the alkyl radicals optionally form with the nitrogen atom to which they are attached a heterocycle to 4- to 7-membered chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl or azepinyl either R2 and R ₃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle chosen from the azetidine, pyrrolidine, piperidine, morpholine and piperazine rings optionally substituted by an alkyl radical, 2) or ------- represents a double bond, X represents an oxygen atom and Z represents a radical of general formula:

defined as follows: a) either R ₁ and R ₅ each represent a hydrogen atom and R ₄ represents a pyrrolidinyl-3 thio or piperidyl-3 or 4 thio radical (these radicals being optionally substituted by an alkyl radical) or else R ₄ represents a radical alkylthio substituted by one or two hydroxysulfonyl, alkyloyino, dialkoylamino radicals (optionally substituted by a mercapto or dialkoylamino radical) or by one or two rings chosen from piperazino (optionally substituted by an alkyl or mercaptoalkyl radical), morpholino, thiomorpholino, piperidino, pyrérolidino 1, piperidyl-2, 3 or 4 and pyrrolidinyl-2 or 3 (these last two cycles being optionally substituted on the nitrogen atom by an alkyl radical), b) either R ₁ and R ₅ together form a valence bond and R ₄ represents a pyrrolidinyl-3 amino, piperidyl-3 or 4 amino radical, pyrrolidinyl-3 oxy, piperidyl-3 or 4 oxy, pyrrolidinyl-3 thio, piperidyl -3 or 4 thio (these radicals being optionally substituted on the ring nitrogen atom by an alkyl radical), or else R ₄ represents an alkyllamino, alkyloxy or alkylthio radical substituted by one or two hydroxysulfonyl, alkyllamino, dialkoylamino radicals ( optionally substituted by a dialkoylamino), trialcoylammonio or imidazolyle-4 or 5 radical or by one or two rings chosen from piperazino (optionally substituted by an alkyl or mercaptoalkyl), morpholino, thiomorpholino, piperidino, pyrrolidinyl-1, piperidyl-2, 3 radical or 4 and pyrrolidinyl-2 or 3 (these last two cycles being optionally substituted on the nitrogen atom by an alkyl radical), it being understood that the alkyl radicals and alkyl portions referring to the symbols defined above conti have 1 to 5 carbon atoms and are in a straight or branched chain, where appropriate in the form of one of its isomers or of mixtures thereof, and optionally in the form of an addition salt with an acid, a metal salt or an addition salt with an organic nitrogenous base, said composition possibly also containing other pharmaceutically acceptable adjuvants. A process for the preparation of new pristinamycin II _B derivatives of general formula:

in which R represents - or a substituted alkylthio radical: - i) by one or two alkylamino or dialkoylamino radicals, the alkyl parts of which may optionally form, together with the nitrogen atom to which they are linked, a saturated heterocycle chosen from pyrrolidinyl-1, piperidino, azetidinyl-1, azepinyl-1, morpholino , thiomorpholino and piperazinyl-1 (optionally substituted by an alkyl radical), or else ii) by a pyrrolidinyl-2 or 3, piperidyl-2, 3 or 4, azetidinyl-2 or 3 or azeepinyl-2, 3 or 4 radical, - either a radical of general formula:

in which Het represents a pyrrolidinyl-3 piperidyl-3 or 4, azetidinyl-3 or azepinyl-3 or 4 radical (optionally substituted on the nitrogen atom by an alkyl radical) - or a dialkoylamino radical, the alkyl parts of which may optionally form, together with the nitrogen atom to which they are linked, a saturated heterocycle chosen from pyrrolidinyl-1, piperidino, azetidinyl-1, azepinyl-1, morpholino, thiomorpholino and piperazinyl-1 (optionally substituted by an alkyl radical), it being understood that the radicals and alkyl portions mentioned above contain 1 to 5 carbon atoms in a straight or branched chain, the. where appropriate in their isomeric forms and their mixtures, as well as their addition salts with acids, pharmaceutically acceptable, characterized in that a product of general formula is made to act:

in which R is defined as above on pristinamycin II _A of formula:

then, where appropriate, separates the isomers from the product obtained and optionally transforms it into an addition salt with an acid, which is pharmaceutically acceptable.